HAEM5:Acute myeloid leukaemia with CBFB::MYH11 fusion: Difference between revisions
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{{DISPLAYTITLE:Acute myeloid leukaemia with CBFB::MYH11 fusion}} | {{DISPLAYTITLE:Acute myeloid leukaemia with CBFB::MYH11 fusion}} | ||
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]] | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | ||
{{Under Construction}} | {{Under Construction}} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Acute Myeloid Leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11]]. | ||
}}</blockquote> | }}</blockquote> | ||
<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span> | |||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
| Line 11: | Line 14: | ||
<br> | <br> | ||
Beth Israel Deaconess Medical Center, Boston, MA | Beth Israel Deaconess Medical Center, Boston, MA | ||
==WHO Classification of Disease== | |||
{| class="wikitable" | |||
!Structure | |||
= | !Disease | ||
|- | |||
|Book | |||
|Haematolymphoid Tumours (5th ed.) | |||
|- | |||
|Category | |||
|Myeloid proliferations and neoplasms | |||
|- | |||
|Family | |||
|Acute myeloid leukaemia | |||
|- | |||
|Type | |||
|Acute myeloid leukaemia with defining genetic abnormalities | |||
|- | |||
|Subtype(s) | |||
|Acute myeloid leukaemia with CBFB::MYH11 fusion | |||
|} | |||
Acute myeloid leukaemia | |||
== | ==Related Terminology== | ||
{| class="wikitable" | {| class="wikitable" | ||
| | |+ | ||
| | |Acceptable | ||
|Acute myeloid leukaemia with CBFB rearrangement; acute myeloid leukaemia with t(16;16)(p13.1;q22); acute myeloid leukaemia with inv(16)(p13.1q22) | |||
|- | |- | ||
| | |Not Recommended | ||
| | |N/A | ||
|} | |} | ||
== | ==Gene Rearrangements== | ||
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> | |||
= | |||
< | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
! | !Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s) | ||
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | |||
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | |||
!Established Clinical Significance Per Guidelines - Yes or No (Source) | |||
!Clinical Relevance Details/Other Notes | |||
|- | |- | ||
| | |<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2) | ||
|<span class="blue-text">EXAMPLE:</span> Common (CML) | |||
|<span class="blue-text">EXAMPLE:</span> D, P, T | |||
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN) | |||
|<span class="blue-text">EXAMPLE:</span> | |||
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference). | |||
|- | |- | ||
| | |<span class="blue-text">EXAMPLE:</span> ''CIC'' | ||
| | |<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4'' | ||
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''. | |||
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13) | |||
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma) | |||
|<span class="blue-text">EXAMPLE:</span> D | |||
| | |||
|<span class="blue-text">EXAMPLE:</span> | |||
''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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|} | |} | ||
Put content below into table above... | |||
* | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
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*Standard induction 7 + 3 chemotherapy regimen of cytarabine for 7 days plus an anthracycline or anthracenedione for 3 days. In first complete remission patients younger than 60 years without a KIT mutation are treated with at least three courses of high dose cytarabine. If a ''KIT'' mutation is present, bone marrow transplant is performed in first complete remission<ref>{{Cite journal|last=Yoon|first=J.-H.|last2=Kim|first2=H.-J.|last3=Kim|first3=J.-W.|last4=Jeon|first4=Y.-W.|last5=Shin|first5=S.-H.|last6=Lee|first6=S.-E.|last7=Cho|first7=B.-S.|last8=Eom|first8=K.-S.|last9=Kim|first9=Y.-J.|date=2014-12|title=Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation|url=https://pubmed.ncbi.nlm.nih.gov/25111512|journal=Bone Marrow Transplantation|volume=49|issue=12|pages=1466–1474|doi=10.1038/bmt.2014.180|issn=1476-5365|pmid=25111512}}</ref>. Other therapies under investigation include gemtuzumab ozogamicin, histone deacetylase inhibitors, DNA methyl transferase inhibitors, proteasome inhibition and tyrosine kinase inhibitors<ref name=":1" />. | *Standard induction 7 + 3 chemotherapy regimen of cytarabine for 7 days plus an anthracycline or anthracenedione for 3 days. In first complete remission patients younger than 60 years without a KIT mutation are treated with at least three courses of high dose cytarabine. If a ''KIT'' mutation is present, bone marrow transplant is performed in first complete remission<ref>{{Cite journal|last=Yoon|first=J.-H.|last2=Kim|first2=H.-J.|last3=Kim|first3=J.-W.|last4=Jeon|first4=Y.-W.|last5=Shin|first5=S.-H.|last6=Lee|first6=S.-E.|last7=Cho|first7=B.-S.|last8=Eom|first8=K.-S.|last9=Kim|first9=Y.-J.|date=2014-12|title=Identification of molecular and cytogenetic risk factors for unfavorable core-binding factor-positive adult AML with post-remission treatment outcome analysis including transplantation|url=https://pubmed.ncbi.nlm.nih.gov/25111512|journal=Bone Marrow Transplantation|volume=49|issue=12|pages=1466–1474|doi=10.1038/bmt.2014.180|issn=1476-5365|pmid=25111512}}</ref>. Other therapies under investigation include gemtuzumab ozogamicin, histone deacetylase inhibitors, DNA methyl transferase inhibitors, proteasome inhibition and tyrosine kinase inhibitors<ref name=":1" />. | ||
|}[[File:t(16;16)(p13.1;q22).png|t(16;16)(p13.1;q22)|frame|alt=|left]] [[File:inv(16)(p13.1q22).png|inv(16)(p13.1q22)|frame|alt=|left]] [[File:Inv(16)(p13.1q22) karyogram and insert (8-7-18).png|inv(16)(p13.1q22). Courtesy of Karen Kundinger, Comprehensive Genetic Services, Milwaukee, WI|frame|alt=|none]] | |||
inv(16)(p13.1q22), a pericentric inversion of chromosome 16, and the less common t(16;16)(p13.1;q22), a translocation involving the short arm of one chromosome 16 and the long arm of the other chromosome 16, define a distinctive cytogenetic subtype of acute myeloid leukemia. Both of these chromosome rearrangements result in the CBFB-MYH11 gene fusion. | |||
* | |||
==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> | |||
{| class="wikitable sortable" | |||
|- | |||
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s) | |||
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | |||
!Established Clinical Significance Per Guidelines - Yes or No (Source) | |||
!Clinical Relevance Details/Other Notes | |||
|- | |||
|<span class="blue-text">EXAMPLE:</span> | |||
7 | |||
|<span class="blue-text">EXAMPLE:</span> Loss | |||
|<span class="blue-text">EXAMPLE:</span> | |||
chr7 | |||
|<span class="blue-text">EXAMPLE:</span> | |||
Unknown | |||
|<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. | |||
|- | |||
| | |||
| | |||
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|} | |} | ||
inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is the sole chromosome aberration in approximately 60% of cases. | inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is the sole chromosome aberration in approximately 60% of cases. | ||
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|} | |} | ||
==Characteristic Chromosomal 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> | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Chromosomal Pattern | !Chromosomal Pattern | ||
! | !Molecular Pathogenesis | ||
!Prognostic Significance | !Prevalence - | ||
! | Common >20%, Recurrent 5-20% or Rare <5% (Disease) | ||
!Notes | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | ||
!Established Clinical Significance Per Guidelines - Yes or No (Source) | |||
!Clinical Relevance Details/Other Notes | |||
|- | |- | ||
|EXAMPLE | |<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> Common (Oligodendroglioma) | |||
|<span class="blue-text">EXAMPLE:</span> D, P | |||
| | |||
| | |||
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> | |||
Microsatellite instability - hypermutated | |||
| | |||
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma) | |||
|<span class="blue-text">EXAMPLE:</span> P, T | |||
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|- | |||
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|} | |} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Patterns|The content below was from the previous version of the page. Please incorporate above.}}</blockquote> | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
!Chromosomal Pattern | !Chromosomal Pattern | ||
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|} | |} | ||
<blockquote class="blockedit"> | |||
<center><span style="color:Maroon">'''End of V4 Section'''</span> | |||
---- | |||
</blockquote> | </blockquote> | ||
==Gene Mutations (SNV / INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
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" | |||
|- | |||
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence - | |||
Common >20%, Recurrent 5-20% or Rare <5% (Disease) | |||
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | |||
!Established Clinical Significance Per Guidelines - Yes or No (Source) | |||
!Clinical Relevance Details/Other Notes | |||
|- | |||
|<span class="blue-text">EXAMPLE:</span>''EGFR'' | |||
<br /> | |||
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations | |||
|<span class="blue-text">EXAMPLE:</span> Oncogene | |||
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer) | |||
|<span class="blue-text">EXAMPLE:</span> T | |||
|<span class="blue-text">EXAMPLE:</span> 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). | |||
|- | |||
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations | |||
<br /> | |||
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations | |||
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene | |||
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer) | |||
|<span class="blue-text">EXAMPLE:</span> P | |||
| | |||
|<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 | |||
|<span class="blue-text">EXAMPLE:</span> Activating mutations | |||
|<span class="blue-text">EXAMPLE:</span> Oncogene | |||
|<span class="blue-text">EXAMPLE:</span> Common (melanoma) | |||
|<span class="blue-text">EXAMPLE:</span> T | |||
| | |||
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|- | |||
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|}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. | |||
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) has genetic heterogeneity at the molecular level. Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis. | AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) has genetic heterogeneity at the molecular level. Several genes have been identified that are frequently mutated in this subset of AML, some of them adversely affecting prognosis. | ||
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{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Gene; Genetic Alteration!! | !Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC / TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations | ||
! | !Diagnostic Significance (Yes, No or Unknown) | ||
!Prognostic Significance (Yes, No or Unknown) | !Prognostic Significance (Yes, No or Unknown) | ||
!Therapeutic Significance (Yes, No or Unknown) | !Therapeutic Significance (Yes, No or Unknown) | ||
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==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: | |||
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> | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | ||
|- | |- | ||
|EXAMPLE: BRAF and MAP2K1; Activating mutations | |<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations | ||
|EXAMPLE: MAPK signaling | |<span class="blue-text">EXAMPLE:</span> MAPK signaling | ||
|EXAMPLE: Increased cell growth and proliferation | |<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation | ||
|- | |||
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations | |||
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation | |||
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division | |||
|- | |- | ||
|EXAMPLE: | |<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations | ||
|EXAMPLE: | |<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling | ||
|EXAMPLE: | |<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program | ||
|- | |- | ||
| | | | ||
| | | | ||
| | | | ||
|} | |} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the previous version of the page. Please incorporate above.}}</blockquote> | ||
''CBFB'' (core binding factor β) on 16q22 is transcribed from centromere to telomere. It codes for CBFβ, a subunit of the transcription factor complex core binding factor. CBFβ by itself does not contain any DNA binding motif or transcriptional activation domain, but forms a dimer with ''CBFa'' (''RUNX1'') which is a transcription factor . ''MYH11'' (smooth muscle myosin heavy-chain gene) on 16p13.1 is transcribed from centromere to telomere, contains a N-term ATPase head responsible for actin binding and mechanical movement, and a C-terminus long repeat of coil-coil domain to facilitate filament aggregates; member of the myosin II family. | ''CBFB'' (core binding factor β) on 16q22 is transcribed from centromere to telomere. It codes for CBFβ, a subunit of the transcription factor complex core binding factor. CBFβ by itself does not contain any DNA binding motif or transcriptional activation domain, but forms a dimer with ''CBFa'' (''RUNX1'') which is a transcription factor . ''MYH11'' (smooth muscle myosin heavy-chain gene) on 16p13.1 is transcribed from centromere to telomere, contains a N-term ATPase head responsible for actin binding and mechanical movement, and a C-terminus long repeat of coil-coil domain to facilitate filament aggregates; member of the myosin II family. | ||
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Protein: A fusion protein with the first 165 (or 133 in a few cases) amino acids of the N-terminus of CBFβ, minus only 17 or 22 amino acids, fused to the tail of the MYH11 C-terminus with its multimerization domain. The breakpoint in ''MYH11'' is variable. The fusion protein retains the ability to dimerize with ''RUNX1'' in the heterodimeric core binding factor. The core binding factor is a transcription factor that plays an essential role in regulation of normal hematopoiesis. It is composed of a DNA-binding ''CBFα'' (''RUNX1'') chain and a non-DNA-binding CBFβ chain. It is likely oncogenic due to altered transcriptional regulation of normal ''RUNX1'' target genes. Animal studies suggest that the fusion proteins alone are not able to induce leukemia and that additional genetic alterations are required for leukemogenic transformation<ref>{{Cite journal|last=Downing|first=James R.|date=2003-02|title=The core-binding factor leukemias: lessons learned from murine models|url=https://pubmed.ncbi.nlm.nih.gov/12573435|journal=Current Opinion in Genetics & Development|volume=13|issue=1|pages=48–54|doi=10.1016/s0959-437x(02)00018-7|issn=0959-437X|pmid=12573435}}</ref>. | Protein: A fusion protein with the first 165 (or 133 in a few cases) amino acids of the N-terminus of CBFβ, minus only 17 or 22 amino acids, fused to the tail of the MYH11 C-terminus with its multimerization domain. The breakpoint in ''MYH11'' is variable. The fusion protein retains the ability to dimerize with ''RUNX1'' in the heterodimeric core binding factor. The core binding factor is a transcription factor that plays an essential role in regulation of normal hematopoiesis. It is composed of a DNA-binding ''CBFα'' (''RUNX1'') chain and a non-DNA-binding CBFβ chain. It is likely oncogenic due to altered transcriptional regulation of normal ''RUNX1'' target genes. Animal studies suggest that the fusion proteins alone are not able to induce leukemia and that additional genetic alterations are required for leukemogenic transformation<ref>{{Cite journal|last=Downing|first=James R.|date=2003-02|title=The core-binding factor leukemias: lessons learned from murine models|url=https://pubmed.ncbi.nlm.nih.gov/12573435|journal=Current Opinion in Genetics & Development|volume=13|issue=1|pages=48–54|doi=10.1016/s0959-437x(02)00018-7|issn=0959-437X|pmid=12573435}}</ref>. | ||
<blockquote class="blockedit"> | |||
<center><span style="color:Maroon">'''End of V4 Section'''</span> | |||
---- | |||
</blockquote> | </blockquote> | ||
==Genetic Diagnostic Testing Methods== | ==Genetic Diagnostic Testing Methods== | ||
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==Additional Information== | ==Additional Information== | ||
This disease is <u>defined/characterized</u> as detailed below: | |||
Acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) resulting in CBFB-MYH11 gene fusion is a subtype of AML with granulocytic and monocytic differentiation and abnormal bone marrow eosinophils. In the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, it is in the group of AML with recurrent genetic abnormalities<ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=05 19, 2016|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://pubmed.ncbi.nlm.nih.gov/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref>. In the older French-American-British (FAB) classification system, inv(16)(p13.1q22) or t(16;16)(p13.1;q22) positive AML belonged to the acute myelomonocytic leukemia with abnormal bone marrow eosinophils M4e category. inv(16)(p13.1q22) or t(16;16)(p13.1;q22) can occasionally be seen in therapy-related AML and in blast phase of chronic myelogenous leukemia. In those instances, the leukemia is not classified in the group of AML with recurrent genetic abnormalities due to clinical and prognostic differences. | |||
*inv(16)(p13.1q22), a pericentric inversion of chromosome 16, and the less common t(16;16)(p13.1;q22), a translocation involving the short arm of one chromosome 16 and the long arm of the other chromosome 16, define a distinctive cytogenetic subtype of acute myeloid leukemia. Both of these chromosome rearrangements result in the CBFB-MYH11 gene fusion. | |||
*Occurs in all age groups but predominantly in younger patients. | |||
*Myeloid sarcoma may be present at initial diagnosis or at relapse and in some patients may constitute the only evidence of relapse. | |||
*inv(16)(p13.1q22) is a subtle chromosome rearrangement that may not be appreciated when chromosome morphology is suboptimal. | |||
*Cases with a cryptic CBFB-MYH11 gene rearrangement are possible. | |||
*A deletion within 16p13 accompanying a rearrangement of 16p13 and 16q22 occurs in 20% of cases<ref>{{Cite journal|last=Marlton|first=P.|last2=Claxton|first2=D. F.|last3=Liu|first3=P.|last4=Estey|first4=E. H.|last5=Beran|first5=M.|last6=LeBeau|first6=M.|last7=Testa|first7=J. R.|last8=Collins|first8=F. S.|last9=Rowley|first9=J. D.|date=1995-02-01|title=Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis|url=https://pubmed.ncbi.nlm.nih.gov/7833479|journal=Blood|volume=85|issue=3|pages=772–779|issn=0006-4971|pmid=7833479}}</ref><ref>{{Cite journal|last=Martinet|first=D.|last2=Mühlematter|first2=D.|last3=Leeman|first3=M.|last4=Parlier|first4=V.|last5=Hess|first5=U.|last6=Gmür|first6=J.|last7=Jotterand|first7=M.|date=1997-07|title=Detection of 16 p deletions by FISH in patients with inv(16) or t(16;16) and acute myeloid leukemia (AML)|url=https://pubmed.ncbi.nlm.nih.gov/9204976|journal=Leukemia|volume=11|issue=7|pages=964–970|doi=10.1038/sj.leu.2400681|issn=0887-6924|pmid=9204976}}</ref>. | |||
*Loss of 3’ ''CBFB'' occurs in 4-8% of cases of ''CBFB'' rearranged AML. Of these cases, 69-73% are positive for CBFB-MYH11 fusion by RT-PCR <ref>{{Cite journal|last=Yang|first=Richard K.|last2=Toruner|first2=Gokce A.|last3=Wang|first3=Wei|last4=Fang|first4=Hong|last5=Issa|first5=Ghayas C.|last6=Wang|first6=Lulu|last7=Quesada|first7=Andrés E.|last8=Thakral|first8=Beenu|last9=Patel|first9=Keyur P.|date=2021-10-26|title=CBFB Break-Apart FISH Testing: An Analysis of 1629 AML Cases with a Focus on Atypical Findings and Their Implications in Clinical Diagnosis and Management|url=https://pubmed.ncbi.nlm.nih.gov/34771519|journal=Cancers|volume=13|issue=21|pages=5354|doi=10.3390/cancers13215354|issn=2072-6694|pmc=8582369|pmid=34771519}}</ref><ref>{{Cite journal|last=Lv|first=Lili|last2=Yu|first2=Jingwei|last3=Qi|first3=Zhongxia|date=2020|title=Acute myeloid leukemia with inv(16)(p13.1q22) and deletion of the 5'MYH11/3'CBFB gene fusion: a report of two cases and literature review|url=https://pubmed.ncbi.nlm.nih.gov/32015759|journal=Molecular Cytogenetics|volume=13|pages=4|doi=10.1186/s13039-020-0474-9|issn=1755-8166|pmc=6990480|pmid=32015759}}</ref><ref>{{Cite journal|last=Kelly|first=Johanna|last2=Foot|first2=Nicola J.|last3=Conneally|first3=Eibhlin|last4=Enright|first4=Helen|last5=Humphreys|first5=Mervyn|last6=Saunders|first6=Karen|last7=Neat|first7=Michael J.|date=2005-10-15|title=3'CBFbeta deletion associated with inv(16) in acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/16213359|journal=Cancer Genetics and Cytogenetics|volume=162|issue=2|pages=122–126|doi=10.1016/j.cancergencyto.2005.03.001|issn=0165-4608|pmid=16213359}}</ref><ref>{{Cite journal|last=Tang|first=Guilin|last2=Zou|first2=Ying|last3=Wang|first3=Sa A.|last4=Borthakur|first4=Gautam|last5=Toruner|first5=Gokce|last6=Hu|first6=Shimin|last7=Li|first7=Shaoying|last8=Xu|first8=Jie|last9=Medeiros|first9=L. Jeffrey|date=2022-04|title=3'CBFB deletion in CBFB-rearranged acute myeloid leukemia retains morphological features associated with inv(16), but patients have higher risk of relapse and may require stem cell transplant|url=https://pubmed.ncbi.nlm.nih.gov/35184217|journal=Annals of Hematology|volume=101|issue=4|pages=847–854|doi=10.1007/s00277-022-04767-1|issn=1432-0584|pmid=35184217}}</ref>. | |||
The <u>epidemiology/prevalence</u> of this disease is detailed below: | |||
*Approximately 5-8% of AML cases have inv(16)(p13.1q22) or t(16;16)(p13.1;q22). More common in males and younger adults. | |||
The <u>clinical features</u> of this disease are detailed below: | |||
Signs and symptoms - May present as myeloid sarcoma | |||
Laboratory findings - Abnormal eosinophil component (bone marrow); Leukocytosis | |||
The <u>sites of involvement</u> of this disease are detailed below: | |||
*Bone marrow | |||
The <u>morphologic features</u> of this disease are detailed below: | |||
*Bone marrow shows the usual morphologic features of acute myelomonocytic leukemia. | |||
*Eosinophils at all stages of maturation are usually increased. | |||
*Eosinophilic granules at the promyelocyte and myelocyte stages are larger than usual and often have a purple-violet color. They may be so dense as to obscure the nucleus. | |||
*Mature eosinophils may occasionally show nuclear hyposegmentation. | |||
*Abnormal eosinophils are not usually seen in the peripheral blood. | |||
*Auer rods may be present in myeloblasts. | |||
*Occasional cases do not have eosinophilia or exhibit only myeloid maturation without a monocytic component or only monocytic maturation. | |||
[[File:Inv_16_pathology.png|frame|center|Bone marrow aspirate with inv(16)(p13.1q22) positive myeloblasts and abnormal immature | |||
eosinophils (100X). Robert Willim, MD, Beth Israel Deaconess Medical Center, Boston, MA | |||
]]The <u>immunophenotype</u> of this disease is detailed below: | |||
*Naphthol-ASD-chloroacetate esterase reaction, which is negative in normal eosinophils, is faintly positive in the abnormal eosinophils. | |||
*≥3% of blasts show myeloperoxidase activity. | |||
*Monoblasts and promonoblasts usually show non-specific esterase activity. | |||
Often a complex immunophenotype with multiple blast populations is seen in: | |||
*immature blasts with high CD34 and CD117 expression | |||
*populations with granulocytic differentiation positive for CD13, CD33, CD15, CD65 and MPO | |||
*populations with monocytic differentiation, positive for CD14, CD4, CD11c, CD11b, CD11c, CD64, CD36 and lysozyme | |||
==Links== | ==Links== | ||
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<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with CBFB::MYH11 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_CBFB::MYH11_fusion</nowiki>. | <nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with CBFB::MYH11 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_CBFB::MYH11_fusion</nowiki>. | ||
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]] | [[Category:HAEM5]] | ||
[[Category:DISEASE]] | |||
[[Category:Diseases A]] | |||