View source for HAEM4Backup:Acute Myeloid Leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

==Primary Author(s)*==

Christine Bryke, MD
<br>
Beth Israel Deaconess Medical Center, Boston, MA

__TOC__

==Cancer Category/Type==

Acute myeloid leukemia

==Cancer Sub-Classification / Subtype==

Acute myeloid leukaemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) resulting in 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)||
|}

==Chromosomal Rearrangements (Gene Fusions)==

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|inv(16)(p13.1q22) or t(16;16)(p13.1;q22)||5'CBFB / 3'MYH11||der(16)||5-8% of AML
|Yes
|Yes
|No
|Diagnostic

*The presence of inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is diagnostic of a cytogenetic subtype of AML with granulocytic and monocytic differentiation and abnormal bone marrow eosinophils.
*When inv(16)(p13.1q22) or t(16;16)(p13.1;q22) are present the diagnosis of acute myeloid leukemia is made regardless of a blast count less than 20%.

Per 2022 International Consensus Classification of Myeloid Neoplasms and Acute Leukemias guidelines, blast count needs to be  at least 10% or more <ref>{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert P.|last4=Borowitz|first4=Michael J.|last5=Calvo|first5=Katherine R.|last6=Kvasnicka|first6=Hans-Michael|last7=Wang|first7=Sa A.|last8=Bagg|first8=Adam|last9=Barbui|first9=Tiziano|date=2022-09-15|title=International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data|url=https://ashpublications.org/blood/article/140/11/1200/485730/International-Consensus-Classification-of-Myeloid|journal=Blood|language=en|volume=140|issue=11|pages=1200–1228|doi=10.1182/blood.2022015850|issn=0006-4971|pmc=PMC9479031|pmid=35767897}}</ref>


Prognostic

*inv(16)(p13.1q22) and t(16;16)(p13.1;q22) positive AML usually has a good response to chemotherapy and a high complete remission rate with long-term disease-free survival when treated with high dose cytarabine in the consolidation phase.  Older age and ''KIT'' gene mutations adversely affected prognosis.  The prognostic significance of other accompanying gene mutations is under investigation<ref name=":0" />.
*FLT3-TKD tyrosine kinase domain mutation and trisomy 8 are associated with a worse outcome.


Recent data demonstrate that the presence of kinase pathway variants (''FLT3'' (TKD and ITD), ''RAS'', or ''KIT'') or additional cytogenetic abnormalities (other than -Y) occurring in patients with CBF-rearranged AML treated with FLAG-based regimens was not an adverse prognostic factor <ref>{{Cite journal|last=Senapati|first=Jayastu|last2=Abuasab|first2=Tareq|last3=Haddad|first3=Fadi G.|last4=Ravandi|first4=Farhad|last5=Kadia|first5=Tapan|last6=DiNardo|first6=Courtney|last7=Daver|first7=Naval|last8=Pemmaraju|first8=Naveen|last9=Alvarado|first9=Yesid|date=2023-03|title=Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G‐CSF based regimens|url=https://onlinelibrary.wiley.com/doi/10.1002/ajh.26811|journal=American Journal of Hematology|language=en|volume=98|issue=3|doi=10.1002/ajh.26811|issn=0361-8609}}</ref>.


Therapeutic target

*AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) currently has no molecular target for drug therapy.
*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" />.

|}

==Individual Region Genomic Gain/Loss/LOH==

inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is the sole chromosome aberration in approximately 60% of cases.

{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|8
|Gain
|chr8:1-145,138,636 [hg38]
|chr8
|No
|No
|No
|Frequently observed. Does not adversely affect the favorable prognosis associated with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) unless a KIT gene mutation is also present (see below)
|-
|22
|Gain
|chr22:1-50,818,468 [hg38]
|chr22
|No
|No
|No
|Frequently observed. Does not adversely affect the favorable prognosis associated with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) unless a KIT gene mutation is also present (see below)
|-
|21
|Gain
|chr21:1-46,709,983 [hg38]
|chr21
|No
|No
|No
|Occasionally observed. Does not adversely affect the favorable prognosis associated with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) unless a KIT gene mutation is also present (see below)
|-
|7
|Loss
|chr7:60,100,001-159,345,973 [hg38]
|chr7q
|No
|No
|No
|Occasionally observed. Does not adversely affect the favorable prognosis associated with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) unless a KIT gene mutation is also present (see below)
|}

==Characteristic Chromosomal Patterns==
{| class="wikitable sortable"
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|Not Applicable
|N/A
|N/A
|N/A
|N/A
|}

==Gene Mutations (SNV/INDEL)==

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.

{| class="wikitable sortable"
|-
!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)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|KIT; Gain of Function mutations in exons 8 or 17
|Proto-Oncogene
|30%<ref name=":0">{{Cite journal|last=Paschka|first=Peter|last2=Marcucci|first2=Guido|last3=Ruppert|first3=Amy S.|last4=Mrózek|first4=Krzysztof|last5=Chen|first5=Hankui|last6=Kittles|first6=Rick A.|last7=Vukosavljevic|first7=Tamara|last8=Perrotti|first8=Danilo|last9=Vardiman|first9=James W.|date=2006-08-20|title=Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study|url=https://pubmed.ncbi.nlm.nih.gov/16921041|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=24|issue=24|pages=3904–3911|doi=10.1200/JCO.2006.06.9500|issn=1527-7755|pmid=16921041}}</ref>
|N/A
|N/A
|No
|Yes
|
|The ''KIT'' gene on 4q12 encodes a transmembrane glycoprotein that activates signaling pathways involved in cellular proliferation, differentiation and survival. Associated with a high risk of relapse in cases of AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22). Patients with ''KIT'' mutations have a significantly shorter overall survival and disease free survival periods than those without ''KIT'' mutations.  Gene expression profile analysis of ''KIT'' mutation positive core binding factor AML showed dysregulation of genes belonging to the ''NF-κB'' signaling complex indicating impairment of apoptosis<ref name=":1">{{Cite journal|last=Solh|first=Melhem|last2=Yohe|first2=Sophia|last3=Weisdorf|first3=Daniel|last4=Ustun|first4=Celalettin|date=2014-12|title=Core-binding factor acute myeloid leukemia: Heterogeneity, monitoring, and therapy|url=https://pubmed.ncbi.nlm.nih.gov/25088818|journal=American Journal of Hematology|volume=89|issue=12|pages=1121–1131|doi=10.1002/ajh.23821|issn=1096-8652|pmid=25088818}}</ref>.<br>
|}
		
===Other Mutations===

Mutations in ''NRAS'' (45%), ''KRAS'' and ''FLT3'' (''FLT3''-TKD and ''FLT3''-ITD) have also been found in inv(16)(p13.1q22) or t(16;16)(p13.1;q22) AML<ref>{{Cite journal|last=Paschka|first=Peter|last2=Du|first2=Juan|last3=Schlenk|first3=Richard F.|last4=Gaidzik|first4=Verena I.|last5=Bullinger|first5=Lars|last6=Corbacioglu|first6=Andrea|last7=Späth|first7=Daniela|last8=Kayser|first8=Sabine|last9=Schlegelberger|first9=Brigitte|date=2013-01-03|title=Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)|url=https://pubmed.ncbi.nlm.nih.gov/23115274|journal=Blood|volume=121|issue=1|pages=170–177|doi=10.1182/blood-2012-05-431486|issn=1528-0020|pmid=23115274}}</ref>. Recently a ''FLT3'' N676K mutation has been identified in a small subset of the disease<ref>{{Cite journal|last=Opatz|first=Sabrina|last2=Polzer|first2=Harald|last3=Herold|first3=Tobias|last4=Konstandin|first4=Nikola P.|last5=Ksienzyk|first5=Bianka|last6=Zellmeier|first6=Evelyn|last7=Vosberg|first7=Sebastian|last8=Graf|first8=Alexander|last9=Krebs|first9=Stefan|date=2013-09-05|title=Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23878140|journal=Blood|volume=122|issue=10|pages=1761–1769|doi=10.1182/blood-2013-01-476473|issn=1528-0020|pmid=23878140}}</ref><ref>{{Cite journal|last=Huang|first=Kezhi|last2=Yang|first2=Min|last3=Pan|first3=Zengkai|last4=Heidel|first4=Florian H.|last5=Scherr|first5=Michaela|last6=Eder|first6=Matthias|last7=Fischer|first7=Thomas|last8=Büsche|first8=Guntram|last9=Welte|first9=Karl|date=2016-04|title=Leukemogenic potency of the novel FLT3-N676K mutant|url=https://pubmed.ncbi.nlm.nih.gov/26891877|journal=Annals of Hematology|volume=95|issue=5|pages=783–791|doi=10.1007/s00277-016-2616-z|issn=1432-0584|pmid=26891877}}</ref>. In addition, ''TET2'' mutations have been identified<ref>{{Cite journal|last=Cher|first=C. Y.|last2=Leung|first2=G. M. K.|last3=Au|first3=C. H.|last4=Chan|first4=T. L.|last5=Ma|first5=E. S. K.|last6=Sim|first6=J. P. Y.|last7=Gill|first7=H.|last8=Lie|first8=A. K. W.|last9=Liang|first9=R.|date=07 08, 2016|title=Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome|url=https://pubmed.ncbi.nlm.nih.gov/27391574|journal=Blood Cancer Journal|volume=6|issue=7|pages=e442|doi=10.1038/bcj.2016.51|issn=2044-5385|pmc=5030377|pmid=27391574}}</ref> and ''WT1'' mutations have been found to be relatively common (13.8%) in inv(16) core-binding factor leukemia<ref>{{Cite journal|last=Park|first=Sang Hyuk|last2=Lee|first2=Hyun Ji|last3=Kim|first3=In-Suk|last4=Kang|first4=Jeong-Eun|last5=Lee|first5=Eun Yup|last6=Kim|first6=Hyeoung-Joon|last7=Kim|first7=Yeo-Kyeoung|last8=Won|first8=Jong-Ho|last9=Bang|first9=Soo Mee|date=2015-05|title=Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean Population|url=https://pubmed.ncbi.nlm.nih.gov/25932436|journal=Annals of Laboratory Medicine|volume=35|issue=3|pages=288–297|doi=10.3343/alm.2015.35.3.288|issn=2234-3814|pmc=4390696|pmid=25932436}}</ref>. ''CBL'' mutations are less common and can be seen in ~5% of patients with inv(16) AML<ref name=":2">{{Cite journal|last=Allen|first=C.|last2=Hills|first2=R. K.|last3=Lamb|first3=K.|last4=Evans|first4=C.|last5=Tinsley|first5=S.|last6=Sellar|first6=R.|last7=O'Brien|first7=M.|last8=Yin|first8=J. L.|last9=Burnett|first9=A. K.|date=2013-09|title=The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23783394|journal=Leukemia|volume=27|issue=9|pages=1891–1901|doi=10.1038/leu.2013.186|issn=1476-5551|pmid=23783394}}</ref>.

*Negative for ''ASXL2'' mutation [which is common in t(8;21)].

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

==Epigenomic Alterations==

None

==Genes and Main Pathways Involved==

''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.


DNA: inv(16)(p13.1q22) and t(16;16)(p13.1;q22) result in the CBFB-MYH11 hybrid gene involving fusion of 5’ ''CBFB'' in intron 5 and variable breakpoints in ''MYH11''.


mRNA: At least 8 different CBFB-MYH11 fusion transcripts have been described. A transcript with ''CBFB'' and ''MYH11'' positions at nucleotides 495 and 1921, respectively, is found in about 90% of patients.  There is no reciprocal MYH11-CBFB transcript.


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>.

==Genetic Diagnostic Testing Methods==

Chromosome analysis for inversion or translocation; FISH or RT-PCR for CBFB-MYH11 gene fusion rearrangement.

FISH or RT-PCR for CBFB-MYH11 is needed when chromosome morphology is suboptimal and for cytogenetically cryptic cases with typical bone marrow morphology and immunophenotype. 

<br>
[[File:Inv_16_FISH.png|frame|center|FISH with CBFB break apart probe set on interphase cells with inv(16)(p13.1q22).
Craig Kanaugh, Comprehensive Genetic Services,Milwaukee, WI.]]
<br>

*RT-PCR for CBFB-MYH11 is employed for minimal residual disease detection. The attainment of optimal PCR response (OPR) of <0.1% PCR transcripts (at a level of detection of 10-4 ) after induction (C1) and <0.01% during or following consolidation has led to improved relapse-free survival (RFS)<ref>{{Cite journal|last=Boddu|first=Prajwal|last2=Gurguis|first2=Christopher|last3=Sanford|first3=David|last4=Cortes|first4=Jorge|last5=Akosile|first5=Mary|last6=Ravandi|first6=Farhad|last7=Garcia-Manero|first7=Guillermo|last8=Patel|first8=Keyur P|last9=Kadia|first9=Tapan|date=2018-06-08|title=Response kinetics and factors predicting survival in core-binding factor leukemia|url=http://dx.doi.org/10.1038/s41375-018-0158-1|journal=Leukemia|volume=32|issue=12|pages=2698–2701|doi=10.1038/s41375-018-0158-1|issn=0887-6924}}</ref><ref>{{Cite journal|last=Yin|first=John A. Liu|last2=O'Brien|first2=Michelle A.|last3=Hills|first3=Robert K.|last4=Daly|first4=Sarah B.|last5=Wheatley|first5=Keith|last6=Burnett|first6=Alan K.|date=2012-10-04|title=Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial|url=http://dx.doi.org/10.1182/blood-2012-06-435669|journal=Blood|volume=120|issue=14|pages=2826–2835|doi=10.1182/blood-2012-06-435669|issn=0006-4971}}</ref>
*In ''KIT'' mutation positive cases detection of the ''KIT'' mutation should not be used for assessment minimal residual disease because ''KIT'' mutations are frequently lost at relapse<ref name=":2" />.

==Familial Forms==

None

==Additional Information==

None

==Links==

[[CBFB]]

[[MYH11]]

http://www.uptodate.com/contents/cytogenetics-in-acute-myeloid-leukemia<br>http://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:1539

http://www.clevelandclinicmeded.com. 

==References==
<references />
==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.


[[Category:Translocation]]
[[Category:Translocation Chromosome 16]]
[[Category:Inversion]]
[[Category:Inversion Chromosome 16]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 16]]
[[Category:Fusion Genes in AML]]
[[Category:Fusion Genes C]]
[[Category:Fusion Genes M]]
[[Category:Recently Added Pages]]

Edited by: Fabiola Quintero-Rivera 7/21/2018