inv(16)(p13q22) CBFB/MYH11
t(16;16)(p13;q22) CBFB/MYH11
del(16)(q22) CBFB/MYH11

1999-06-01   Jean-Loup Huret  

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology

Disease

acute non lymphoblastic leukaemia (AML); myelodysplastic syndromes (MDS) at times

Phenotype stem cell origin

nearly pathognomonic of M4eo-AML (all M4eo share the 16q22 anomaly -see also below-, but not all 16p13/16q22 are found in the M4eo subtype: i.e. this anomaly, although mainly found in M4-AML with marked eosinophilia, may (rarely) been found in : M2 or M5, M4 without eo, or in MDS; there are also known cases of chronic myelogenous leukaemia in blast crisis (BC-CML) with a M4 eo phenotype and inv(16); found at times in treatment related AML; 3 cases of infant leukaemia so far described; note: CD2 (T-cell marker) may be co-expressed

Epidemiology

5-10% of AML, 20% of M4

Clinics

CNS involvement is frequent, according to some authors, in particular at relapse

Cytology

most often: eosinophils > 5%, with large immature basophilic granules, NASCA+, in the bone marrow (but normal in blood: this M4 do not show the eo characteristic in blood)
Atlas Image
Patients with inv(16) usually correspond to the subclass of AML M4, with a specific abnormal eosinophil component and is considered as a distinct entity in correlation with these specific chromosomal abnormalities. These cases of AML M4 are referred as AML M4EO. In addition to the morphological features of AML M4 excess of monocytes), the bone marrow shows a variable number of eosinophils at all stages of maturation without significant maturation arrest. The most striking abnormalities involve the immature eosinophilic granules. Those are mainly evident at the promyelocyte and myelocyte stages. The abnormalities are not usually evident at later stages of maturation. These eosinophilic granules are often larger than those normally seen in immature eosinophils, purple-violet in color and in some cells are so dense that they obscure the cell morphology - Text and iconography Courtesy Georges Flandrin 2001.

Prognosis

high CR rate; better prognosis than most other AML; median survival may be 5yrs

Cytogenetics

Cytogenetics morphological

may be overlooked, especially with R-banding; best seen without banding procedure (giemsa) for some workers

Cytogenetics molecular

with 16p13 probes : as a deletion within 16p13 often accompany the 16p13/16q22 rearrangement (in 20% of cases), the split signal may be lost

Additional anomalies

none 2/3 of cases; +8, +22 in 15% each, del(7q), +2; apparently without prognostic significance

Variants

are known:
1- t(16;16)(p13;q22);
- del(16)(q22): may be associated with less typical phenotype and preceding MDS, older age, complex karyotype, worse prognosis;

2- but also: translocations of 16q22 with various partners in: t(1;16)(p31-32;q22), t(3;16)(q21;q22), t(5;16)(q33;q22), associated with eosinophils anomalies

Genes Involved and Proteins

Gene name
MYH11 (myosin heavy chain) (incomplete)
Location
16p13.11
Atlas Image
c-MYH11 (16p13) in normal cells: PAC 1032E3 (top) and PAC 1179J13 (below) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Protein description
contains a N-term ATPase head responsible for actin binding and mechanical movement, and a C-term long repeat of coil-coil domain to facilitate filament aggregates; member of the myosin II family
Gene name
CBFB (subunit b of core binding factor)
Location
16q22.1
Protein description
subunit of the transcription factor complex CBF; CBFb by itself does not contain any DNA binding motif or transcriptional activation domain, but forms a dimer with CBFa: --> transcription factor

Result of the Chromosomal Anomaly

Description

5 CBFb - 3 MYH11; breakpoint in CBFB intron n° 5 and in MYH11 intron A (i.e. : 5)

Transcript

at least 8 different CBFb-MYH11 fusion transcripts have been described, transcript type A (with positions at nucleotides 495 and 1921 respectively) being found in about 90% of the patients;most braekpoints in MYH11 are also clustered; no reciprocal MYH11-CBFB transcript

Description

N-term - the first 165 (or 133 in a few cases) amino acids of CBFb, removing only 17 or 22 amino acids fused to the tail of MYH11 C-term with its multimerization domain; also variable breakpoint in MYH11; identical fusion protein in the cases of RAEBT and BC-CML

Expression localisation

nuclear localisation

Oncogenesis

the fusion protein seems both to diminuish the quantity of active CBF and to compete with it, there is accumulation of CBFb-MYH11/CBFa multimeres in the nucleus

Highly cited references

Pubmed IDYearTitleCitations
277986252016The genomic landscape of core-binding factor acute myeloid leukemias.110
304425032018Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.81
318967822020The clinical mutatome of core binding factor leukemia.28
278431382017Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.28
276949262017NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis.28
299322122018CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia.20
318997992020Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11.19
328312962020CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia.15
320921392020Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801.14
272983962016Comparison of Multiparameter Flow Cytometry Immunophenotypic Analysis and Quantitative RT-PCR for the Detection of Minimal Residual Disease of Core Binding Factor Acute Myeloid Leukemia.14
290180802017Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11.13
280307952017AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis.11
316124662020Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.10
295325202018Clinicopathological characteristics of de novo and secondary myeloid sarcoma: A monocentric retrospective study.10
318966842021Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia.9
302771152019Panoramic view of common fusion genes in a large cohort of Chinese de novo acute myeloid leukemia patients.9
284754342017Enhancing acute myeloid leukemia therapy - monitoring response using residual disease testing as a guide to therapeutic decision-making.9
316243762020Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice.8
295175042018Somatic Mutations and Intratumoral Heterogeneity of MYH11 Gene in Gastric and Colorectal Cancers.8
282535362017Myeloid neoplasms with concurrent BCR-ABL1 and CBFB rearrangements: A series of 10 cases of a clinically aggressive neoplasm.8
282996582017Clinical Relevance of RUNX1 and CBFB Alterations in Acute Myeloid Leukemia and Other Hematological Disorders.8
329294732020RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development.7
276505112018Monitoring of post-transplant CBFB-MYH11 as minimal residual disease, rather than KIT mutations, can predict relapse after allogeneic haematopoietic cell transplantation in adults with inv(16) acute myeloid leukaemia.7
346866642021Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance.6
318179112019Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription.6
290677512018Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia.6
285670732017Quantitative assessment of Wilms tumor 1 expression by real-time quantitative polymerase chain reaction in patients with acute myeloblastic leukemia.6
325884342021The loss or absence of minimal residual disease of <0·1% at any time after two cycles of consolidation chemotherapy in CBFB-MYH11-positive acute myeloid leukaemia indicates poor prognosis.5
326523282020IL-33/IL1RL1 axis regulates cell survival through the p38 MAPK pathway in acute myeloid leukemia.5
321755992020Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia.5
316714342020Myeloid Sarcoma With CBFB-MYH11 Fusion (inv(16) or t(16;16)) Prevails in the Abdomen.5
309195052019Measurable residual disease testing for personalized treatment of acute myeloid leukemia.5
300062582018Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician.5
307420532019IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells and promotes cell survival.5
297559562018Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia.5
274600492016Development of a NanoString assay to detect leukemogenic fusion transcripts in acute myeloid leukemia.5
276329782016Multiplexed automated digital quantification of fusion transcripts: comparative study with fluorescent in-situ hybridization (FISH) technique in acute leukemia patients.5
345465432022All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16.4
321016402020Significance of minimal residual disease monitoring by real-time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes.4
308141292019HDAC1 Is a Required Cofactor of CBFβ-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia.4
289060042017Acute myeloid leukaemia (FAB AML-M4Eo) with cryptic insertion of cbfb resulting in cbfb-Myh11 fusion.4
334746292021Both the subtypes of KIT mutation and minimal residual disease are associated with prognosis in core binding factor acute myeloid leukemia: a retrospective clinical cohort study in single center.3
291052432018Multiplex fusion gene testing in pediatric acute myeloid leukemia.3
346383012021Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia.2
340821592021Comparable Outcomes After Alternative and Matched Sibling Donor Hematopoietic Stem Cell Transplantation and the Role of Molecular Measurable Residual Disease for Acute Myeloid Leukemia in Elderly Patients.2
338365812021Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.2
332087712020RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia.2
324193642020Clinical and immunological features of platelet transfusion refractoriness in young patients with de novo acute myeloid leukemia.2
307284572019Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine.2
306100522018Synchronous Diagnosis of De Novo Acute Myeloid Leukemia with inv(16)(p13q22) and Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature.2
282996612017Molecular Basis and Targeted Inhibition of CBFβ-SMMHC Acute Myeloid Leukemia.2
287354862017Detection and Quantification of Acute Myeloid Leukemia-Associated Fusion Transcripts.2
341837802021Prognostic values of D816V KIT mutation and peri-transplant CBFB-MYH11 MRD monitoring on acute myeloid leukemia with CBFB-MYH11.1
3518421720223'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.1
347715192021CBFB Break-Apart FISH Testing: An Analysis of 1629 AML Cases with a Focus on Atypical Findings and Their Implications in Clinical Diagnosis and Management.1
346602932021Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia.1
341170742021Incidental identification of inv(16)(p13.1q22)/CBFB-MYH11 variant transcript in a patient with therapy-related acute myeloid leukemia by routine leukemia translocation panel screen: implications for diagnosis and therapy.1
325792872020Blastic transformation of BCR-ABL1 positive chronic myeloid leukaemia through acquisition of CBFB-MYH11 and mutant KIT.1
313531652020Detection of a novel CBFB-MYH11 fusion transcript in acute myeloid leukemia M1 with inv(16)(p13q22).1
324920022020[Driver Mutations in Acute Myeloid Leukemia with Inversion of Chromosome 16].1
308099812019The Incidence and Immunophenotypic and Genetic Features of JL1 Expressing Cells and the Therapeutic Potential of an Anti-JL1 Antibody in De Novo Pediatric Acute Leukemias.1
307014582019Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon: a 10-year experience report and review of the literature.1
285798542017Acute Myeloid Leukemia With Inv(16)(p13q22) Associated With Hidden Systemic Mastocytosis: Case Report and Review of Literature.1
288832852017Genetic abnormalities in core binding factor acute myeloid leukemia.1
356135012022Jumping translocation involving chromosome 13q in a patient with Crohn's Disease and inv(16)(p13.1q22)/CBFB-MYH11 acute myeloid leukemia.0
358848342022Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group.0
354455942022Comprehensive Mutation Profile in Acute Myeloid Leukemia Patients with RUNX1-RUNX1T1 or CBFB-MYH11 Fusions0
351286342022TET2 deficiency cooperates with CBFB-MYH11 to induce acute myeloid leukaemia and represents an early leukaemogenic event.0
346749822022Prognostic of Core Binding Factor (CBF) Acute Myeloid Leukemia With Complex Karyotype.0
359739832022Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia.0
359188242022Fusion transcript analysis reveals slower response kinetics than multiparameter flow cytometry in childhood acute myeloid leukaemia.0
356220052022AML with inv(16)/t(16;16) and high-risk cytogenetic abnormalities: atypical features and unfavorable outcome.0
360112782022PPP1R7 Is a Novel Translocation Partner of CBFB via t(2;16)(q37;q22) in Acute Myeloid Leukemia.0
359078962022Acute hepatitis-like presentation with cholestasis of CBFB-MYH11-positive acute myeloid leukemia in an adult male: a case report.0
357945672022Molecular dissection of a hyper-aggressive CBFB-MYH11/FLT3-ITD-positive acute myeloid leukemia.0
354979382022Therapy-related acute myeloid leukemia: A case series.0
355317602022Combination of KIT and FLT3-ITD mutation status with minimal residual disease levels guides treatment strategy for adult patients with inv(16) acute myeloid leukemia in first complete remission.0
342724862021Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission.0
337308432022Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.0
345129852021Abnormal eosinophils with immature eosinophilic granules in chronic myeloid leukemia in accelerated phase.0
352511312022Fusion Gene Detection Using Whole-Exome Sequencing Data in Cancer Patients.0
346746152021Clinical values of gene alterations as marker of minimal residual disease in non-M3 acute myeloid leukemia.0
345477722021CBFB-MYH11 fusion transcripts distinguish acute myeloid leukemias with distinct molecular landscapes and outcomes.0
322022502021Detection of del(16q) using the CBFB-MYH11 translocation dual fusion probe.0
348044412021Gastrointestinal Myeloid Sarcoma a Case Presentation and Review of the Literature.0
338161052021Primary peritoneal myeloid sarcoma in association with CBFB/MYH11 fusion.0
344401572021How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring.0
343368312021CBFB-MYH11 Fusion Sequesters RUNX1 in Cytoplasm to Prevent DNMT3A Recruitment to Target Genes in AML.0
335003642020Molecular Monitoring in Acute Myeloid Leukemia Patients Undergoing Matched Unrelated Donor - Hematopoietic Stem Cell Transplantation: Single Center Experience.0
333037202021A Case of Acute Myeloid Leukemia With inv(16)(p13.1q22);CBFB-MYH11 Presenting With Faggot Cells.0
332049992020Identification of Fusion Gene Breakpoints is Feasible and Facilitates Accurate Sensitive Minimal Residual Disease Monitoring on Genomic Level in Patients With PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1.0
334893892020De Novo Acute Myeloid Leukemia with Combined CBFB-MYH11 and BCR-ABL1 Gene Rearrangements: A Case Report and Review of Literature.0
326691712020[Clinical features and prognosis of core binding factor acute myeloid leukemia in children].0
322234882020Cytogenetically masked CBFB-MYH11 fusion and concomitant TP53 deletion in a case of acute myeloid leukemia with a complex karyotype.0
331625102020[Clinical significance of MRD in AML].0
317210362020Mature neutrophils with Auer rod bundles in CBFB-MYH11-positive acute myeloid leukemia.0
325449102020Truncated RUNX1 Generated by the Fusion of RUNX1 to Antisense GRIK2 via a Cryptic Chromosome Translocation Enhances Sensitivity to Granulocyte Colony-Stimulating Factor.0
313998072019BCR-ABL1- and CBFB-MYH11-positive chronic myeloid leukemia presenting with primary blast crisis and marrow fibrosis.0
283754342017Most Myeloid Neoplasms With Deletion of Chromosome 16q Are Distinct From Acute Myeloid Leukemia With Inv(16)(p13.1q22): A Bone Marrow Pathology Group Multicenter Study.0
306953132016[Case Conference of Hematological Malignancies Based on the Morphology of Blood Cells: Chairmen's Introductory Remarks].0

Article Bibliography

Pubmed IDLast YearTitleAuthors
27792891989Acute nonlymphocytic leukemia with marrow eosinophilia and chromosome 16 abnormality: a report of 18 cases.Bernard P et al
14537701992Abnormalities of chromosome 16q in myeloid malignancy: 14 new cases and a review of the literature.Betts DR et al
20699091991Chromosome 16 abnormalities associated with myeloid malignancies.Campbell LJ et al
82689051993Cloning the breakpoint cluster region of the inv(16) in acute nonlymphocytic leukemia M4 Eo.Dauwerse JG et al
83389411993Identification of yeast artificial chromosomes containing the inversion 16 p-arm breakpoint associated with acute myelomonocytic leukemia.Liu P et al
77277631995Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia.Liu PP et al
77801531995Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia.Shurtleff SA et al
99272111999Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered.van der Reijden BA et al

Summary

Fusion gene

CBFB/MYH11 CBFB (16q22.1) MYH11 (16p13.11) M ins(16)(q22p13p13) ins(16;16)(q22;p13p13) inv(16)(p13q22) t(16;16)(p13;q22)|CBFB/MYH11 CBFB (16q22.1) MYH11 (16p13.11) TIC

Note

the three chromosome anomalies are variants of each other, and they share identical clinical features and genetic pathogenesis
Atlas Image
TOP: inv(16)(p13q22) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen; R- banding center bottom: - Courtesy Christiane Charrin, center top and FISH (middle right) - Courtesy Pascale Cornillet-Lefebvre and Stephanie Struski; FISH (right) - Courtesy Hossein Mossafa; commercial FISH probes, split in the inv(16). BOTTOM: t(16;16)(p13;q22) G-banding - left two - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services; middle two and FSIH Vysis LSI CBFB Dual Color, Break Apart Rearrangement Probe ?nuc ish(CBFBx2)(5CBFB sep 3CBFBx1) - Courtesy Ian Brooks and Jackie Challis, Oncology Cytogenetics, Victorian Clinical Genetics Services, Australia.

Citation

Jean-Loup Huret

inv(16)(p13q22) CBFB/MYH11
t(16;16)(p13;q22) CBFB/MYH11
del(16)(q22) CBFB/MYH11

Atlas Genet Cytogenet Oncol Haematol. 1999-06-01

Online version: http://atlasgeneticsoncology.org/haematological/1036/haematological-explorer/cancer-prone-explorer/humanGenome

Historical Card

1997-11-01 inv(16)(p13q22) CBFB/MYH11
t(16;16)(p13;q22) CBFB/MYH11
del(16)(q22) CBFB/MYH11 by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France