Acute Myeloid Leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Christine Bryke, MD
Beth Israel Deaconess Medical Center, Boston, MA
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. 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.
- 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 .
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.
|Signs and Symptoms||May present as myeloid sarcoma|
|Laboratory Findings||Abnormal eosinophil component (bone marrow)
Sites of Involvement
- 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.
- 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 (granulocytic differentiation)||CD13, CD33, CD15, CD65 and MPO|
|Positive (monocytic differentiation)||CD14, CD4, CD11c, CD11b, CD11c, CD64, CD36 and lysozyme|
Chromosomal Rearrangements (Gene Fusions)
|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
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.
|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
|Chromosomal Pattern||Diagnostic Significance (Yes, No or Unknown)||Prognostic Significance (Yes, No or Unknown)||Therapeutic Significance (Yes, No or Unknown)||Notes|
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.
|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%||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.|
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. Recently a FLT3 N676K mutation has been identified in a small subset of the disease. In addition, TET2 mutations have been identified and WT1 mutations have been found to be relatively common (13.8%) in inv(16) core-binding factor leukemia. CBL mutations are less common and can be seen in ~5% of patients with inv(16) AML.
- 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.
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.
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.
- RT-PCR for CBFB-MYH11 is employed for minimal residual disease detection.
- 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.
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*Citation of this Page: Bryke C. “Acute Myeloid Leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 10/28/2022, https://ccga.io/index.php/Acute Myeloid Leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11.
Edited by: Fabiola Quintero-Rivera 7/21/2018