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

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/inv(16)(p13q22)

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

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