Compendium of Cancer Genome Aberrations

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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 (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<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 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>
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|Subtype(s)
|Subtype(s)
|Acute myeloid leukaemia with CBFB::MYH11 fusion
|Acute myeloid leukaemia with CBFB::MYH11 fusion
|}
==Definition / Description of Disease==
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>.
<br>
<br>
[[File:t(16;16)(p13.1;q22).png|t(16;16)(p13.1;q22)|frame|center]] [[File:inv(16)(p13.1q22).png|inv(16)(p13.1q22)|frame|center]] [[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|center]]
==Synonyms / Terminology==
Acute myeloid leukaemia (AML) with inv(16)(p13.1q22); AML, t(16;16)(p13.1;q22);AML,CBFB-MYH11; Acute myelomonocytic leukemia with abnormal eosinophils; FAB classification M4Eo
==Epidemiology / Prevalence==
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.
==Clinical Features==
{| class="wikitable"
|'''Signs and Symptoms'''
|May present as myeloid sarcoma
|-
|'''Laboratory Findings'''
|Abnormal eosinophil component (bone marrow)
Leukocytosis
|}
==Sites of Involvement==
Bone marrow
==Morphologic Features==
*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.
<br>
[[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
]]
<br>
==Immunophenotype==
*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
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (granulocytic differentiation)||CD13, CD33, CD15, CD65 and MPO
|-
|Positive (monocytic differentiation)
|CD14, CD4, CD11c, CD11b, CD11c, CD64, CD36 and lysozyme
|-
|Positive (subset)||
|-
|Negative (universal)||
|-
|Negative (subset)||
|}
|}


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|}[[File:t(16;16)(p13.1;q22).png|t(16;16)(p13.1;q22)|frame|center]] [[File:inv(16)(p13.1q22).png|inv(16)(p13.1q22)|frame|center]] [[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|center]]


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<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>
<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>
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<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>
<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==


None
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
 
Positive (universal) -
 
Positive (majority) -
 
Positive (subset) -
 
Negative (universal) -
 
Negative (subset) -


==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>.
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[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases A]]
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