HAEM5:Acute myeloid leukaemia with CBFB::MYH11 fusion: Difference between revisions
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<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> | ||
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<br> | <br> | ||
Beth Israel Deaconess Medical Center, Boston, MA | Beth Israel Deaconess Medical Center, Boston, MA | ||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
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|} | |} | ||
== | ==Related Terminology== | ||
{| class="wikitable" | {| class="wikitable" | ||
|+ | |+ | ||
|Acceptable | |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 | |Not Recommended | ||
| | |N/A | ||
|} | |} | ||
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Put content below into table above... | |||
* | |||
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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== | ==Individual Region Genomic Gain/Loss/LOH== | ||
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{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Chr #!! | !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> | |<span class="blue-text">EXAMPLE:</span> | ||
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!Chromosomal Pattern | !Chromosomal Pattern | ||
!Molecular Pathogenesis | !Molecular Pathogenesis | ||
! | !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> | |<span class="blue-text">EXAMPLE:</span> | ||
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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> | </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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|} | |} | ||
<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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==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]] | |||