Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with CEBPA mutation: Difference between revisions

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==WHO Essential and Desirable Genetic Diagnostic Criteria==
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
{| class="wikitable"
|+
|+
|WHO Essential Criteria (Genetics)*
|WHO Essential Criteria (Genetics)*
|
|>= 20% blasts with a myeloid immunophenotype in the bone marrow or blood; presence of biallelic mutations in ''CEBPA (''bi''CEBPA)'', or a single mutation located in the bZIP region (smbZIP-''CEBPA''); absence of criteria allowing for classification into other AMLs with defining genetic abnormalities; not fulling diagnostic criteria for myeloid neoplasm post cytotoxic therapy.
|-
|-
|WHO Desirable Criteria (Genetics)*
|WHO Desirable Criteria (Genetics)*
|
|NA
|-
|-
|Other Classification
|Other Classification
Line 50: Line 49:
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
{| class="wikitable"
|+
|+
|Acceptable
|Acceptable
|
|acute myeloid leukaemia with biallelic mutation of ''CEBPA.''
|-
|-
|Not Recommended
|Not Recommended
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Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
None.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|
|
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|
|
|}
|}
<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
None
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 5%
|-
|<span class="blue-text">EXAMPLE:</span> t(8;21)(q22;q22)||<span class="blue-text">EXAMPLE:</span> 5'RUNX1 / 3'RUNXT1||<span class="blue-text">EXAMPLE:</span> der(8)||<span class="blue-text">EXAMPLE:</span> 5%
|}
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>
Patients with biallelic ''CEBPA'' mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no ''CEBPA'' mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p142-144.</ref>.
Patients with abnormal karyotypes (but not complex karyotypes) and biallelic ''CEBPA'' mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no ''CEBPA'' mutations<ref name=":0" />.
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==




Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
Subset of cases have abnormal karyotype, del(9q) is common but does not make a diagnosis of AML with myelodysplasia related changes<ref name=":6">{{Cite journal|last=Frohling|first=Stefan|last2=Schlenk|first2=Richard F.|last3=Krauter|first3=Jurgen|last4=Ganser|first4=Arnold|last5=Thiede|first5=Christian|last6=Ehninger|first6=Gerhard|last7=Haase|first7=Detlef|last8=Harder|first8=Lana|last9=Scholl|first9=Claudia|date=2004-11-16|title=Acute Myeloid Leukemia with Deletion 9q Is Associated with CEBPA Loss-of-Function Mutations.|url=https://www.sciencedirect.com/science/article/pii/S0006497118667941|journal=Blood|volume=104|issue=11|pages=2896|doi=10.1182/blood.V104.11.2896.2896|issn=0006-4971}}</ref><ref name=":7">{{Cite journal|last=Fröhling|first=Stefan|last2=Schlenk|first2=Richard F.|last3=Krauter|first3=Jürgen|last4=Thiede|first4=Christian|last5=Ehninger|first5=Gerhard|last6=Haase|first6=Detlef|last7=Harder|first7=Lana|last8=Kreitmeier|first8=Sylvia|last9=Scholl|first9=Claudia|date=2005|title=Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations|url=https://onlinelibrary.wiley.com/doi/10.1002/gcc.20152|journal=Genes, Chromosomes and Cancer|language=en|volume=42|issue=4|pages=427–432|doi=10.1002/gcc.20152|issn=1098-2264}}</ref>.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!'''Clinical Relevance Details/Other Notes'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|9
7
|Loss
|<span class="blue-text">EXAMPLE:</span> Loss
|9q
|<span class="blue-text">EXAMPLE:</span>
|Unknown
chr7
|P
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|A collaborative intergroup study has been initiated to define whether the relatively good prognosis associated with del(9q) is related to the presence of a ''CEBPA'' mutation<ref name=":6" />.
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|
|
|
|
|
|
|
|}
|}
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
None
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|<span class="blue-text">EXAMPLE:</span> 8||<span class="blue-text">EXAMPLE:</span> Gain||<span class="blue-text">EXAMPLE:</span> chr8:0-1000000
|-
|<span class="blue-text">EXAMPLE:</span> 7||<span class="blue-text">EXAMPLE:</span> Loss||<span class="blue-text">EXAMPLE:</span> chr7:0-1000000
|}
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==




Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
None.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!'''Clinical Relevance Details/Other Notes'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span> Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
Line 265: Line 152:
|
|
|}
|}
==Gene Mutations (SNV/INDEL)==


<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>


None
Patients with biallelic ''CEBPA'' mutations and a normal karyotype have a more favorable prognosis than those with monoallelic or no ''CEBPA'' mutations, with higher complete remission rates and longer disease-free survival, relapse-free survival, event-free survival, and overall survival<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p142-144.</ref>.
 
Patients with abnormal karyotypes (but not complex karyotypes) and biallelic ''CEBPA'' mutations also have longer disease-free survival, event-free survival, and overall survival when compared to patients with monoallelic or no ''CEBPA'' mutations<ref name=":0" />. Detection of bi''CEBPA'' should raise possibility of germline mutation. Germline testing may be considered in patients with persistent ''CEBPA'' mutations following morphologic remission or in patients with family history of leukemia<ref name=":8">{{Cite journal|last=Tawana|first=Kiran|last2=Wang|first2=Jun|last3=Renneville|first3=Aline|last4=Bödör|first4=Csaba|last5=Hills|first5=Robert|last6=Loveday|first6=Chey|last7=Savic|first7=Aleksandar|last8=Van Delft|first8=Frederik W.|last9=Treleaven|first9=Jennifer|date=2015-09-03|title=Disease evolution and outcomes in familial AML with germline CEBPA mutations|url=https://pubmed.ncbi.nlm.nih.gov/26162409|journal=Blood|volume=126|issue=10|pages=1214–1223|doi=10.1182/blood-2015-05-647172|issn=1528-0020|pmid=26162409}}</ref>.
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Gene Mutations (SNV/INDEL)==


 
Pathogenic mutations in ''CEBPA'' are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. Patients with bi''CEBPA'' and smbZIP-''CEBPA'' are younger and have higher white blood cell counts than those with a single mutation in the N-terminal TAD region<ref name=":5">{{Cite journal|last=Taube|first=Franziska|last2=Georgi|first2=Julia Annabell|last3=Kramer|first3=Michael|last4=Stasik|first4=Sebastian|last5=Middeke|first5=Jan Moritz|last6=Röllig|first6=Christoph|last7=Krug|first7=Utz|last8=Krämer|first8=Alwin|last9=Scholl|first9=Sebastian|date=2022-01-06|title=CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome|url=https://pubmed.ncbi.nlm.nih.gov/34320176|journal=Blood|volume=139|issue=1|pages=87–103|doi=10.1182/blood.2020009680|issn=1528-0020|pmid=34320176}}</ref>. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!'''Clinical Relevance Details/Other Notes'''
!'''Clinical Relevance Details/Other Notes'''
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''CEBPA''


<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|c.939_940insAAG, p.K313_V314insK
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> T
|D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|AML with ''CEBPA'' mutation constitutes ~5% pf pediatric AML and 5-11% adult AML<ref name=":9">{{Cite journal|last=Tarlock|first=Katherine|last2=Lamble|first2=Adam J.|last3=Wang|first3=Yi-Cheng|last4=Gerbing|first4=Robert B.|last5=Ries|first5=Rhonda E.|last6=Loken|first6=Michael R.|last7=Brodersen|first7=Lisa Eidenschink|last8=Pardo|first8=Laura|last9=Leonti|first9=Amanda|date=2021-09-30|title=CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/33951732|journal=Blood|volume=138|issue=13|pages=1137–1147|doi=10.1182/blood.2020009652|issn=1528-0020|pmc=8570058|pmid=33951732}}</ref><ref name=":10">{{Cite journal|last=Wakita|first=Satoshi|last2=Sakaguchi|first2=Masahiro|last3=Oh|first3=Iekuni|last4=Kako|first4=Shinichi|last5=Toya|first5=Takashi|last6=Najima|first6=Yuho|last7=Doki|first7=Noriko|last8=Kanda|first8=Junya|last9=Kuroda|first9=Junya|date=2022-01-11|title=Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/34448807|journal=Blood Advances|volume=6|issue=1|pages=238–247|doi=10.1182/bloodadvances.2021004292|issn=2473-9537|pmc=8753195|pmid=34448807}}</ref><ref name=":5" />.  Accounts for 4 - 9% of AML diagnoses in children and young adults. Less common in older patients.
 
 
AML with ''CEBPA'' mutation is associated with favorable prognosis<ref>Pollyea DA, Altman JK, (2025). NCCN Clinical Practice Guidelines in Oncology: AML. Version 2. Available at: NCCN.org.</ref><ref name=":11">Tumours, 5th edition, IARC Press:Lyon, 2024. Online at: WHO Classification of Tumours.</ref>. bi''CEBPA'' accounts for 2.8% of AML cases, 91% bi''CEBPA'' AML cases with bZIP mutation and favorable prognosis, only 9% bi''CEBPA'' AML cases without bZIP mutation and conflict prognosis<ref>{{Cite journal|last=Wouters|first=Bas J.|last2=Löwenberg|first2=Bob|last3=Erpelinck-Verschueren|first3=Claudia A. J.|last4=van Putten|first4=Wim L. J.|last5=Valk|first5=Peter J. M.|last6=Delwel|first6=Ruud|date=2009-03-26|title=Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome|url=https://pubmed.ncbi.nlm.nih.gov/19171880|journal=Blood|volume=113|issue=13|pages=3088–3091|doi=10.1182/blood-2008-09-179895|issn=1528-0020|pmc=2662648|pmid=19171880}}</ref><ref>{{Cite journal|last=Dufour|first=Annika|last2=Schneider|first2=Friederike|last3=Metzeler|first3=Klaus H.|last4=Hoster|first4=Eva|last5=Schneider|first5=Stephanie|last6=Zellmeier|first6=Evelyn|last7=Benthaus|first7=Tobias|last8=Sauerland|first8=Maria-Cristina|last9=Berdel|first9=Wolfgang E.|date=2010-02-01|title=Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome|url=https://pubmed.ncbi.nlm.nih.gov/20038735|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=28|issue=4|pages=570–577|doi=10.1200/JCO.2008.21.6010|issn=1527-7755|pmid=20038735}}</ref><ref>{{Cite journal|last=Green|first=Claire L.|last2=Koo|first2=Kenneth K.|last3=Hills|first3=Robert K.|last4=Burnett|first4=Alan K.|last5=Linch|first5=David C.|last6=Gale|first6=Rosemary E.|date=2010-06-01|title=Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations|url=https://pubmed.ncbi.nlm.nih.gov/20439648|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=28|issue=16|pages=2739–2747|doi=10.1200/JCO.2009.26.2501|issn=1527-7755|pmid=20439648}}</ref>. Single mutation-''CEBPA'' accounts for 2.3% of AML cases, 32% of ''CEBPA'' single-mutation cases with bZIP mutation and favorable prognosis, while 68% of ''CEBPA'' single-mutation cases without bZIP mutation and show similar prognosis to that of AML with wildtype ''CEBPA''<ref name=":11" />.  smbZIP-''CEBPA'' AML shows similar favorable prognosis with bi''CEBPA'' (Children and adults aged up to 70 years)<ref name=":10" /><ref name=":5" /><ref name=":9" />'','' justifying the inclusion of smbZIP-''CEBPA'' subset''.''
 
 
The treatment approach involves similar induction and consolidation methods as other types of AML, specifically the 7+3 regimen (cytarabine and anthracycline) followed by consolidation with either cytarabine or azacitidine. There may be potential benefits from a stem cell transplant; however, it's important to note that a family member with a germline ''CEBPA'' mutation cannot be used as a donor. Relapsed patients have favorable prognosis as well<ref>{{Cite journal|last=Schlenk|first=Richard F.|last2=Taskesen|first2=Erdogan|last3=van Norden|first3=Yvette|last4=Krauter|first4=Jürgen|last5=Ganser|first5=Arnold|last6=Bullinger|first6=Lars|last7=Gaidzik|first7=Verena I.|last8=Paschka|first8=Peter|last9=Corbacioglu|first9=Andrea|date=2013-08-29|title=The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA|url=https://doi.org/10.1182/blood-2013-05-503847|journal=Blood|volume=122|issue=9|pages=1576–1582|doi=10.1182/blood-2013-05-503847|issn=0006-4971}}</ref>. There is also a propose of a new algorithm for the treatment of these patients, including both familial and sporadic ''CEBPA'' mutated AML patients (Figure3)<ref>{{Cite journal|last=Su|first=Long|last2=Shi|first2=Yuan-Yuan|last3=Liu|first3=Zeng-Yan|last4=Gao|first4=Su-Jun|date=2022|title=Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions|url=https://pubmed.ncbi.nlm.nih.gov/35178345|journal=Frontiers in Oncology|volume=12|pages=806137|doi=10.3389/fonc.2022.806137|issn=2234-943X|pmc=8844020|pmid=35178345}}</ref>.  
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''CEBPA''
<br />
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|c.68_69insC, p.H24fs*84
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> P
|D, P, T
|Yes (NCCN)
|
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|''CEBPA''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|c.247delC, p.Q83fs*77
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Recurrent (AML)
|<span class="blue-text">EXAMPLE:</span> T
|D, P, T
|Yes (NCCN)
|
|
|-
|''CEBPA''
|c.936_937insCAG, p.Q312_K313insQ
|Oncogene
|Recurrent (AML)
|D, P, T
|Yes (NCCN)
|
|
|-
|-
|
|''CEBPA''
|
|c.912_913insTTG, p.K304_Q305insL
|
|Oncogene
|
|Recurrent (AML)
|
|D, P, T
|
|Yes (NCCN)
|
|
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>


Pathogenic mutations in ''CEBPA'' are predominantly insertion/deletion frameshift mutations in the N-terminal TAD region and in-frame C-terminal bZIP mutations. No particular mutational hotspots exist but the following table records the most reported mutations in the COSMIC database (frequency based on a count out of 1523 mutations):
Most of (>70%) cases associated with normal karyotype; del(9q) may also be seen<ref name=":6" /><ref name=":7" />. Concurrent mutations in ''NPM1'' and ''FLT3'' are seen less frequently (5-9%) in individuals with biallelic ''CEBPA'' mutations than in those with no or monoallelic mutations<ref name=":2">{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://www.ncbi.nlm.nih.gov/pubmed/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>. Conversely, mutations in ''GATA2'' appear to occur more often (39%) in ''CEBPA'' single- and double-mutants<ref>{{Cite journal|last=Green|first=Claire L.|last2=Tawana|first2=Kiran|last3=Hills|first3=Robert K.|last4=Bödör|first4=Csaba|last5=Fitzgibbon|first5=Jude|last6=Inglott|first6=Sarah|last7=Ancliff|first7=Phil|last8=Burnett|first8=Alan K.|last9=Linch|first9=David C.|date=2013|title=GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/23560626|journal=British Journal of Haematology|volume=161|issue=5|pages=701–705|doi=10.1111/bjh.12317|issn=1365-2141|pmid=23560626}}</ref>. The prognostic significance of these concomitant mutations is, however, unclear. Biallelic ''CEBPA'' mutations appear to confer a positive prognostic effect regardless of concomitant mutations.
 
{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|''CEBPA''||c.939_940insAAG, p.K313_V314insK||Oncogene||LOF||52
|-
|''CEBPA''||c.68_69insC, p.H24fs*84||Oncogene||LOF||43
|-
|''CEBPA''||c.247delC, p.Q83fs*77||Oncogene||LOF||32
|-
|''CEBPA''||c.936_937insCAG, p.Q312_K313insQ||Oncogene||LOF||28
|-
|''CEBPA''||c.912_913insTTG, p.K304_Q305insL||Oncogene||LOF||24
|}
===Other Mutations===
Concurrent mutations in ''NPM1'' and ''FLT3'' are seen less frequently in individuals with biallelic ''CEBPA'' mutations than in those with no or monoallelic mutations<ref name=":2">{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://www.ncbi.nlm.nih.gov/pubmed/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>. Conversely, mutations in ''GATA2'' appear to occur more often in ''CEBPA'' single- and double-mutants<ref>{{Cite journal|last=Green|first=Claire L.|last2=Tawana|first2=Kiran|last3=Hills|first3=Robert K.|last4=Bödör|first4=Csaba|last5=Fitzgibbon|first5=Jude|last6=Inglott|first6=Sarah|last7=Ancliff|first7=Phil|last8=Burnett|first8=Alan K.|last9=Linch|first9=David C.|date=2013|title=GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/23560626|journal=British Journal of Haematology|volume=161|issue=5|pages=701–705|doi=10.1111/bjh.12317|issn=1365-2141|pmid=23560626}}</ref>. The prognostic significance of these concomitant mutations is, however, unclear. Biallelic ''CEBPA'' mutations appear to confer a positive prognostic effect regardless of concomitant mutations.


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|Mutually Exclusive||None
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<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


None
Mutation types include mutations in the encoding gene and promoter hypermethylation<ref>{{Cite journal|last=Hollink|first=Iris H. I. M.|last2=van den Heuvel-Eibrink|first2=Marry M.|last3=Arentsen-Peters|first3=Susan T. C. J. M.|last4=Zimmermann|first4=Martin|last5=Peeters|first5=Justine K.|last6=Valk|first6=Peter J. M.|last7=Balgobind|first7=Brian V.|last8=Sonneveld|first8=Edwin|last9=Kaspers|first9=Gertjan J. L.|date=2011-03|title=Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21134981|journal=Haematologica|volume=96|issue=3|pages=384–392|doi=10.3324/haematol.2010.031336|issn=1592-8721|pmc=3046269|pmid=21134981}}</ref>.


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==




Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
''CEBPA'', located on chromosome 19 band q13.1, encodes a transcription factor of the basic region leucine zipper (bZIP) family. It is involved in the coordination of myeloid differentiation and cellular growth arrest. Alternative translation initiation sites result in protein isoforms of different lengths.
 
''CEPBA'' works in a tissue-specific manner to direct cellular differentiation by activating lineage-specific gene promoters. Interactions with the basal transcriptional apparatus (TBP/TFIIB), histone acetylators (CBP/p300), and chromatin-remodelling complexes (SWI/SNF) have all been implicated in lineage-specific gene activation by ''CEBPA''. In the haematopoietic system there appears to be interplay between ''CEBPA'' and ''GATA'' factors<ref>{{Cite journal|last=McNagny|first=K. M.|last2=Sieweke|first2=M. H.|last3=Döderlein|first3=G.|last4=Graf|first4=T.|last5=Nerlov|first5=C.|date=1998|title=Regulation of eosinophil-specific gene expression by a C/EBP-Ets complex and GATA-1|url=https://www.ncbi.nlm.nih.gov/pubmed/9649437|journal=The EMBO journal|volume=17|issue=13|pages=3669–3680|doi=10.1093/emboj/17.13.3669|issn=0261-4189|pmc=1170703|pmid=9649437}}</ref>. ''CEBPA'' knockout mice show a complete lack of granulocytes while blasts accumulate in the bone marrow, suggesting an early block of myeloid maturation<ref>{{Cite journal|last=Zhang|first=D. E.|last2=Zhang|first2=P.|last3=Wang|first3=N. D.|last4=Hetherington|first4=C. J.|last5=Darlington|first5=G. J.|last6=Tenen|first6=D. G.|date=1997|title=Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice|url=https://www.ncbi.nlm.nih.gov/pubmed/9012825|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=94|issue=2|pages=569–574|doi=10.1073/pnas.94.2.569|issn=0027-8424|pmc=PMC19554|pmid=9012825}}</ref>. In the context of haematopoietic differentiation, evidence suggests ''CEBPA'' plays a role in regulating the expression of genes encoding growth factor receptors (e.g. granulocyte colony-stimulating factor) and secondary granule proteins (e.g. lactoferrin)<ref>{{Cite journal|last=Radomska|first=H. S.|last2=Huettner|first2=C. S.|last3=Zhang|first3=P.|last4=Cheng|first4=T.|last5=Scadden|first5=D. T.|last6=Tenen|first6=D. G.|date=1998|title=CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors|url=https://www.ncbi.nlm.nih.gov/pubmed/9632814|journal=Molecular and Cellular Biology|volume=18|issue=7|pages=4301–4314|doi=10.1128/mcb.18.7.4301|issn=0270-7306|pmc=PMC109014|pmid=9632814}}</ref><ref>{{Cite journal|last=Zhang|first=P.|last2=Iwama|first2=A.|last3=Datta|first3=M. W.|last4=Darlington|first4=G. J.|last5=Link|first5=D. C.|last6=Tenen|first6=D. G.|date=1998|title=Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/9743535|journal=The Journal of Experimental Medicine|volume=188|issue=6|pages=1173–1184|doi=10.1084/jem.188.6.1173|issn=0022-1007|pmc=2212540|pmid=9743535}}</ref>. It has also been implicated, along with ''NFI-A'', in mediating miR-223 expression<ref>{{Cite journal|last=Fazi|first=Francesco|last2=Rosa|first2=Alessandro|last3=Fatica|first3=Alessandro|last4=Gelmetti|first4=Vania|last5=De Marchis|first5=Maria Laura|last6=Nervi|first6=Clara|last7=Bozzoni|first7=Irene|date=2005|title=A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/16325577|journal=Cell|volume=123|issue=5|pages=819–831|doi=10.1016/j.cell.2005.09.023|issn=0092-8674|pmid=16325577}}</ref>. Studies indicate that ''CEBPA'' is not required for differentiation of granulocytes beyond the granulocyte-monocyte progenitor (GMP) stage, and that ''CEBPA'' controls stem-cell renewal with expression of ''Bmi-1'' elevated in '''CEBPA'' knockouts<ref>{{Cite journal|last=Zhang|first=Pu|last2=Iwasaki-Arai|first2=Junko|last3=Iwasaki|first3=Hiromi|last4=Fenyus|first4=Maris L.|last5=Dayaram|first5=Tajhal|last6=Owens|first6=Bronwyn M.|last7=Shigematsu|first7=Hirokazu|last8=Levantini|first8=Elena|last9=Huettner|first9=Claudia S.|date=2004|title=Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha|url=https://www.ncbi.nlm.nih.gov/pubmed/15589173|journal=Immunity|volume=21|issue=6|pages=853–863|doi=10.1016/j.immuni.2004.11.006|issn=1074-7613|pmid=15589173}}</ref>.
Proliferation arrest also appears to be an important aspect of ''CEBPA'' function via interaction with CDK2/CDK4, upregulation of the p21 (WAF-1/CIP-1/SDI-1) protein and the SWI/SNF complex, and inhibition of the E2F complex<ref>{{Cite journal|last=Pedersen|first=T. A.|last2=Kowenz-Leutz|first2=E.|last3=Leutz|first3=A.|last4=Nerlov|first4=C.|date=2001|title=Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation|url=https://www.ncbi.nlm.nih.gov/pubmed/11731483|journal=Genes & Development|volume=15|issue=23|pages=3208–3216|doi=10.1101/gad.209901|issn=0890-9369|pmc=PMC312836|pmid=11731483}}</ref><ref>{{Cite journal|last=Slomiany|first=B. A.|last2=D'Arigo|first2=K. L.|last3=Kelly|first3=M. M.|last4=Kurtz|first4=D. T.|date=2000|title=C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription|url=https://www.ncbi.nlm.nih.gov/pubmed/10913181|journal=Molecular and Cellular Biology|volume=20|issue=16|pages=5986–5997|doi=10.1128/mcb.20.16.5986-5997.2000|issn=0270-7306|pmc=PMC86075|pmid=10913181}}</ref><ref>{{Cite journal|last=Timchenko|first=N. A.|last2=Wilde|first2=M.|last3=Nakanishi|first3=M.|last4=Smith|first4=J. R.|last5=Darlington|first5=G. J.|date=1996|title=CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein|url=https://www.ncbi.nlm.nih.gov/pubmed/8846917|journal=Genes & Development|volume=10|issue=7|pages=804–815|doi=10.1101/gad.10.7.804|issn=0890-9369|pmid=8846917}}</ref><ref>{{Cite journal|last=Wang|first=H.|last2=Iakova|first2=P.|last3=Wilde|first3=M.|last4=Welm|first4=A.|last5=Goode|first5=T.|last6=Roesler|first6=W. J.|last7=Timchenko|first7=N. A.|date=2001|title=C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4|url=https://www.ncbi.nlm.nih.gov/pubmed/11684017|journal=Molecular Cell|volume=8|issue=4|pages=817–828|doi=10.1016/s1097-2765(01)00366-5|issn=1097-2765|pmid=11684017}}</ref><ref>{{Cite journal|last=Wang|first=Qian-Fei|last2=Cleaves|first2=Rebecca|last3=Kummalue|first3=Tanawan|last4=Nerlov|first4=Claus|last5=Friedman|first5=Alan D.|date=2003|title=Cell cycle inhibition mediated by the outer surface of the C/EBPalpha basic region is required but not sufficient for granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/12730669|journal=Oncogene|volume=22|issue=17|pages=2548–2557|doi=10.1038/sj.onc.1206360|issn=0950-9232|pmid=12730669}}</ref>. This E2F inhibition leads to ''c-myc'' downregulation, which is required for granulocytic regulation<ref>{{Cite journal|last=Johansen|first=L. M.|last2=Iwama|first2=A.|last3=Lodie|first3=T. A.|last4=Sasaki|first4=K.|last5=Felsher|first5=D. W.|last6=Golub|first6=T. R.|last7=Tenen|first7=D. G.|date=2001|title=c-Myc is a critical target for c/EBPalpha in granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/11340171|journal=Molecular and Cellular Biology|volume=21|issue=11|pages=3789–3806|doi=10.1128/MCB.21.11.3789-3806.2001|issn=0270-7306|pmc=PMC87031|pmid=11340171}}</ref>. Mutations in the C-terminal region of ''CEBPA'' abrogate CEBPA-E2F complex function<ref>{{Cite journal|last=Porse|first=B. T.|last2=Pedersen TA|first2=null|last3=Xu|first3=X.|last4=Lindberg|first4=B.|last5=Wewer|first5=U. M.|last6=Friis-Hansen|first6=L.|last7=Nerlov|first7=C.|date=2001|title=E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo|url=https://www.ncbi.nlm.nih.gov/pubmed/11672531|journal=Cell|volume=107|issue=2|pages=247–258|doi=10.1016/s0092-8674(01)00516-5|issn=0092-8674|pmid=11672531}}</ref>.
The precise mechanism by which ''CEBPA'' mutants inhibit granulocytic differentiation in the context of AML is still unclear.
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<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
''CEBPA'', located on chromosome 19 band q13.1, encodes a transcription factor of the basic region leucine zipper (bZIP) family. It is involved in the coordination of myeloid differentiation and cellular growth arrest. Alternative translation initiation sites result in protein isoforms of different lengths.
''CEPBA'' works in a tissue-specific manner to direct cellular differentiation by activating lineage-specific gene promoters. Interactions with the basal transcriptional apparatus (TBP/TFIIB), histone acetylators (CBP/p300), and chromatin-remodelling complexes (SWI/SNF) have all been implicated in lineage-specific gene activation by ''CEBPA''. In the haematopoietic system there appears to be interplay between ''CEBPA'' and ''GATA'' factors<ref>{{Cite journal|last=McNagny|first=K. M.|last2=Sieweke|first2=M. H.|last3=Döderlein|first3=G.|last4=Graf|first4=T.|last5=Nerlov|first5=C.|date=1998|title=Regulation of eosinophil-specific gene expression by a C/EBP-Ets complex and GATA-1|url=https://www.ncbi.nlm.nih.gov/pubmed/9649437|journal=The EMBO journal|volume=17|issue=13|pages=3669–3680|doi=10.1093/emboj/17.13.3669|issn=0261-4189|pmc=1170703|pmid=9649437}}</ref>. ''CEBPA'' knockout mice show a complete lack of granulocytes while blasts accumulate in the bone marrow, suggesting an early block of myeloid maturation<ref>{{Cite journal|last=Zhang|first=D. E.|last2=Zhang|first2=P.|last3=Wang|first3=N. D.|last4=Hetherington|first4=C. J.|last5=Darlington|first5=G. J.|last6=Tenen|first6=D. G.|date=1997|title=Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice|url=https://www.ncbi.nlm.nih.gov/pubmed/9012825|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=94|issue=2|pages=569–574|doi=10.1073/pnas.94.2.569|issn=0027-8424|pmc=PMC19554|pmid=9012825}}</ref>.
In the context of haematopoietic differentiation, evidence suggests ''CEBPA'' plays a role in regulating the expression of genes encoding growth factor receptors (e.g. granulocyte colony-stimulating factor) and secondary granule proteins (e.g. lactoferrin)<ref>{{Cite journal|last=Radomska|first=H. S.|last2=Huettner|first2=C. S.|last3=Zhang|first3=P.|last4=Cheng|first4=T.|last5=Scadden|first5=D. T.|last6=Tenen|first6=D. G.|date=1998|title=CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors|url=https://www.ncbi.nlm.nih.gov/pubmed/9632814|journal=Molecular and Cellular Biology|volume=18|issue=7|pages=4301–4314|doi=10.1128/mcb.18.7.4301|issn=0270-7306|pmc=PMC109014|pmid=9632814}}</ref><ref>{{Cite journal|last=Zhang|first=P.|last2=Iwama|first2=A.|last3=Datta|first3=M. W.|last4=Darlington|first4=G. J.|last5=Link|first5=D. C.|last6=Tenen|first6=D. G.|date=1998|title=Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/9743535|journal=The Journal of Experimental Medicine|volume=188|issue=6|pages=1173–1184|doi=10.1084/jem.188.6.1173|issn=0022-1007|pmc=2212540|pmid=9743535}}</ref>. It has also been implicated, along with ''NFI-A'', in mediating miR-223 expression<ref>{{Cite journal|last=Fazi|first=Francesco|last2=Rosa|first2=Alessandro|last3=Fatica|first3=Alessandro|last4=Gelmetti|first4=Vania|last5=De Marchis|first5=Maria Laura|last6=Nervi|first6=Clara|last7=Bozzoni|first7=Irene|date=2005|title=A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/16325577|journal=Cell|volume=123|issue=5|pages=819–831|doi=10.1016/j.cell.2005.09.023|issn=0092-8674|pmid=16325577}}</ref>. Studies indicate that ''CEBPA'' is not required for differentiation of granulocytes beyond the granulocyte-monocyte progenitor (GMP) stage, and that ''CEBPA'' controls stem-cell renewal with expression of ''Bmi-1'' elevated in '''CEBPA'' knockouts<ref>{{Cite journal|last=Zhang|first=Pu|last2=Iwasaki-Arai|first2=Junko|last3=Iwasaki|first3=Hiromi|last4=Fenyus|first4=Maris L.|last5=Dayaram|first5=Tajhal|last6=Owens|first6=Bronwyn M.|last7=Shigematsu|first7=Hirokazu|last8=Levantini|first8=Elena|last9=Huettner|first9=Claudia S.|date=2004|title=Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha|url=https://www.ncbi.nlm.nih.gov/pubmed/15589173|journal=Immunity|volume=21|issue=6|pages=853–863|doi=10.1016/j.immuni.2004.11.006|issn=1074-7613|pmid=15589173}}</ref>.
Proliferation arrest also appears to be an important aspect of ''CEBPA'' function via interaction with CDK2/CDK4, upregulation of the p21 (WAF-1/CIP-1/SDI-1) protein and the SWI/SNF complex, and inhibition of the E2F complex<ref>{{Cite journal|last=Pedersen|first=T. A.|last2=Kowenz-Leutz|first2=E.|last3=Leutz|first3=A.|last4=Nerlov|first4=C.|date=2001|title=Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation|url=https://www.ncbi.nlm.nih.gov/pubmed/11731483|journal=Genes & Development|volume=15|issue=23|pages=3208–3216|doi=10.1101/gad.209901|issn=0890-9369|pmc=PMC312836|pmid=11731483}}</ref><ref>{{Cite journal|last=Slomiany|first=B. A.|last2=D'Arigo|first2=K. L.|last3=Kelly|first3=M. M.|last4=Kurtz|first4=D. T.|date=2000|title=C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription|url=https://www.ncbi.nlm.nih.gov/pubmed/10913181|journal=Molecular and Cellular Biology|volume=20|issue=16|pages=5986–5997|doi=10.1128/mcb.20.16.5986-5997.2000|issn=0270-7306|pmc=PMC86075|pmid=10913181}}</ref><ref>{{Cite journal|last=Timchenko|first=N. A.|last2=Wilde|first2=M.|last3=Nakanishi|first3=M.|last4=Smith|first4=J. R.|last5=Darlington|first5=G. J.|date=1996|title=CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein|url=https://www.ncbi.nlm.nih.gov/pubmed/8846917|journal=Genes & Development|volume=10|issue=7|pages=804–815|doi=10.1101/gad.10.7.804|issn=0890-9369|pmid=8846917}}</ref><ref>{{Cite journal|last=Wang|first=H.|last2=Iakova|first2=P.|last3=Wilde|first3=M.|last4=Welm|first4=A.|last5=Goode|first5=T.|last6=Roesler|first6=W. J.|last7=Timchenko|first7=N. A.|date=2001|title=C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4|url=https://www.ncbi.nlm.nih.gov/pubmed/11684017|journal=Molecular Cell|volume=8|issue=4|pages=817–828|doi=10.1016/s1097-2765(01)00366-5|issn=1097-2765|pmid=11684017}}</ref><ref>{{Cite journal|last=Wang|first=Qian-Fei|last2=Cleaves|first2=Rebecca|last3=Kummalue|first3=Tanawan|last4=Nerlov|first4=Claus|last5=Friedman|first5=Alan D.|date=2003|title=Cell cycle inhibition mediated by the outer surface of the C/EBPalpha basic region is required but not sufficient for granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/12730669|journal=Oncogene|volume=22|issue=17|pages=2548–2557|doi=10.1038/sj.onc.1206360|issn=0950-9232|pmid=12730669}}</ref>. This E2F inhibition leads to ''c-myc'' downregulation, which is required for granulocytic regulation<ref>{{Cite journal|last=Johansen|first=L. M.|last2=Iwama|first2=A.|last3=Lodie|first3=T. A.|last4=Sasaki|first4=K.|last5=Felsher|first5=D. W.|last6=Golub|first6=T. R.|last7=Tenen|first7=D. G.|date=2001|title=c-Myc is a critical target for c/EBPalpha in granulopoiesis|url=https://www.ncbi.nlm.nih.gov/pubmed/11340171|journal=Molecular and Cellular Biology|volume=21|issue=11|pages=3789–3806|doi=10.1128/MCB.21.11.3789-3806.2001|issn=0270-7306|pmc=PMC87031|pmid=11340171}}</ref>. Mutations in the C-terminal region of ''CEBPA'' abrogate CEBPA-E2F complex function<ref>{{Cite journal|last=Porse|first=B. T.|last2=Pedersen TA|first2=null|last3=Xu|first3=X.|last4=Lindberg|first4=B.|last5=Wewer|first5=U. M.|last6=Friis-Hansen|first6=L.|last7=Nerlov|first7=C.|date=2001|title=E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo|url=https://www.ncbi.nlm.nih.gov/pubmed/11672531|journal=Cell|volume=107|issue=2|pages=247–258|doi=10.1016/s0092-8674(01)00516-5|issn=0092-8674|pmid=11672531}}</ref>.
The precise mechanism by which ''CEBPA'' mutants inhibit granulocytic differentiation in the context of AML is still unclear.
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


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==Familial Forms==
==Familial Forms==


Familial mutations of ''CEBPA'' have been described in several families<ref name=":3">{{Cite journal|last=Smith|first=Matthew L.|last2=Cavenagh|first2=Jamie D.|last3=Lister|first3=T. Andrew|last4=Fitzgibbon|first4=Jude|date=2004|title=Mutation of CEBPA in familial acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15575056|journal=The New England Journal of Medicine|volume=351|issue=23|pages=2403–2407|doi=10.1056/NEJMoa041331|issn=1533-4406|pmid=15575056}}</ref><ref>{{Cite journal|last=Nanri|first=Tomoko|last2=Uike|first2=Naokuni|last3=Kawakita|first3=Toshiro|last4=Iwanaga|first4=Eisaku|last5=Mitsuya|first5=Hiroaki|last6=Asou|first6=Norio|date=2010|title=A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/19953636|journal=Genes, Chromosomes & Cancer|volume=49|issue=3|pages=237–241|doi=10.1002/gcc.20734|issn=1098-2264|pmid=19953636}}</ref><ref>{{Cite journal|last=Sellick|first=G. S.|last2=Spendlove|first2=H. E.|last3=Catovsky|first3=D.|last4=Pritchard-Jones|first4=K.|last5=Houlston|first5=R. S.|date=2005|title=Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15902292|journal=Leukemia|volume=19|issue=7|pages=1276–1278|doi=10.1038/sj.leu.2403788|issn=0887-6924|pmid=15902292}}</ref>. Typically, these are N-terminal mutations that are later joined by a somatic C-terminal mutation on the opposite allele leading to AML.
Familial mutations of ''CEBPA'' have been described in several families<ref name=":3">{{Cite journal|last=Smith|first=Matthew L.|last2=Cavenagh|first2=Jamie D.|last3=Lister|first3=T. Andrew|last4=Fitzgibbon|first4=Jude|date=2004|title=Mutation of CEBPA in familial acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15575056|journal=The New England Journal of Medicine|volume=351|issue=23|pages=2403–2407|doi=10.1056/NEJMoa041331|issn=1533-4406|pmid=15575056}}</ref><ref>{{Cite journal|last=Nanri|first=Tomoko|last2=Uike|first2=Naokuni|last3=Kawakita|first3=Toshiro|last4=Iwanaga|first4=Eisaku|last5=Mitsuya|first5=Hiroaki|last6=Asou|first6=Norio|date=2010|title=A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/19953636|journal=Genes, Chromosomes & Cancer|volume=49|issue=3|pages=237–241|doi=10.1002/gcc.20734|issn=1098-2264|pmid=19953636}}</ref><ref>{{Cite journal|last=Sellick|first=G. S.|last2=Spendlove|first2=H. E.|last3=Catovsky|first3=D.|last4=Pritchard-Jones|first4=K.|last5=Houlston|first5=R. S.|date=2005|title=Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15902292|journal=Leukemia|volume=19|issue=7|pages=1276–1278|doi=10.1038/sj.leu.2403788|issn=0887-6924|pmid=15902292}}</ref>.  Approximately 5-10% of bi''CEBPA'' AML cases have a germline N-terminal<ref>{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011-02-24|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://pubmed.ncbi.nlm.nih.gov/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>. Typically, these are N-terminal mutations that are later joined by a somatic C-terminal mutation on the opposite allele leading to AML. In the familia from, AML has very high penetrance and presents relatively early (median aga: 245.5 years)<ref name=":8" />. There are some notable familial AML-Associated ''CEBPA'' germline pathogenic variants: c.68delC, p.Pro23ArgfsTer137<ref>{{Cite journal|last=Smith|first=Matthew L.|last2=Cavenagh|first2=Jamie D.|last3=Lister|first3=T. Andrew|last4=Fitzgibbon|first4=Jude|date=2004-12-02|title=Mutation of CEBPA in familial acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/15575056|journal=The New England Journal of Medicine|volume=351|issue=23|pages=2403–2407|doi=10.1056/NEJMoa041331|issn=1533-4406|pmid=15575056}}</ref>; c.68dupC, p.His24AlafsTer84<ref>{{Cite journal|last=Sellick|first=G. S.|last2=Spendlove|first2=H. E.|last3=Catovsky|first3=D.|last4=Pritchard-Jones|first4=K.|last5=Houlston|first5=R. S.|date=2005-07|title=Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15902292|journal=Leukemia|volume=19|issue=7|pages=1276–1278|doi=10.1038/sj.leu.2403788|issn=0887-6924|pmid=15902292}}</ref><ref>{{Cite journal|last=Renneville|first=A.|last2=Mialou|first2=V.|last3=Philippe|first3=N.|last4=Kagialis-Girard|first4=S.|last5=Biggio|first5=V.|last6=Zabot|first6=M.-T.|last7=Thomas|first7=X.|last8=Bertrand|first8=Y.|last9=Preudhomme|first9=C.|date=2009-04|title=Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation|url=https://pubmed.ncbi.nlm.nih.gov/18946494|journal=Leukemia|volume=23|issue=4|pages=804–806|doi=10.1038/leu.2008.294|issn=1476-5551|pmid=18946494}}</ref><ref name=":8" />; c.141delC, p.Ala48ProfsTer112<ref name=":1">{{Cite journal|last=Pabst|first=Thomas|last2=Eyholzer|first2=Marianne|last3=Haefliger|first3=Simon|last4=Schardt|first4=Julian|last5=Mueller|first5=Beatrice U.|date=2008-11-01|title=Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/18768433|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=26|issue=31|pages=5088–5093|doi=10.1200/JCO.2008.16.5563|issn=1527-7755|pmid=18768433}}</ref>; c.147_165del19, p.Glu50AlafsTer104<ref>{{Cite journal|last=Debeljak|first=Maruša|last2=Kitanovski|first2=Lidija|last3=Pajič|first3=Tadej|last4=Jazbec|first4=Janez|date=2013-07|title=Concordant acute myeloblastic leukemia in monozygotic twins with germline and shared somatic mutations in the gene for CCAAT-enhancer-binding protein α with 13 years difference at onset|url=https://pubmed.ncbi.nlm.nih.gov/23716546|journal=Haematologica|volume=98|issue=7|pages=e73–74|doi=10.3324/haematol.2012.082578|issn=1592-8721|pmc=3696596|pmid=23716546}}</ref>; c.158delG, p.Gly53AlafsTer107<ref name=":4">{{Cite journal|last=Taskesen|first=Erdogan|last2=Bullinger|first2=Lars|last3=Corbacioglu|first3=Andrea|last4=Sanders|first4=Mathijs A.|last5=Erpelinck|first5=Claudia A. J.|last6=Wouters|first6=Bas J.|last7=van der Poel-van de Luytgaarde|first7=Sonja C.|last8=Damm|first8=Frederik|last9=Krauter|first9=Jürgen|date=2011-02-24|title=Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity|url=https://pubmed.ncbi.nlm.nih.gov/21177436|journal=Blood|volume=117|issue=8|pages=2469–2475|doi=10.1182/blood-2010-09-307280|issn=1528-0020|pmid=21177436}}</ref>; c.189delC, p.Asp63GlufsTer97<ref name=":4" />; c.314_315insT, p.Phe106LeufsTer2<ref name=":1" />; c.932A>C, p.Gln311Pro<ref>{{Cite journal|last=Pathak|first=Anand|last2=Seipel|first2=Katja|last3=Pemov|first3=Alexander|last4=Dewan|first4=Ramita|last5=Brown|first5=Christina|last6=Ravichandran|first6=Sarangan|last7=Luke|first7=Brian T.|last8=Malasky|first8=Michael|last9=Suman|first9=Shalabh|date=2016-07|title=Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family|url=https://pubmed.ncbi.nlm.nih.gov/26721895|journal=Haematologica|volume=101|issue=7|pages=846–852|doi=10.3324/haematol.2015.130799|issn=1592-8721|pmc=5004464|pmid=26721895}}</ref>; c.442G>T, p.Glu148Ter<ref>{{Cite journal|last=Mendoza|first=Hadrian|last2=Chen|first2=Po-Han|last3=Pine|first3=Alexander B.|last4=Siddon|first4=Alexa J.|last5=Bale|first5=Allen E.|last6=Gowda|first6=Lohith|last7=Killie|first7=Amy|last8=Richards|first8=Jonica|last9=Varin-Tremblay|first9=Camille|date=2021-05|title=A case of acute myeloid leukemia with unusual germline CEBPA mutation: lessons learned about mutation detection, location, and penetrance|url=https://pubmed.ncbi.nlm.nih.gov/33345654|journal=Leukemia & Lymphoma|volume=62|issue=5|pages=1251–1254|doi=10.1080/10428194.2020.1861276|issn=1029-2403|pmid=33345654}}</ref>.


==Additional Information==
==Additional Information==


Put your text here
''CEBPA'' stands for CCAAT enhancer-binding protein alpha.


==Links==
==Links==
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