HAEM4Backup:Acute Myeloid Leukemia (AML) with t(4;12)(q12;p13); CHIC2-ETV6
Primary Author(s)*
Paige Woodham, M.D.
Daynna J. Wolff, Ph.D.
Cancer Category/Type
Acute Myeloid Leukemia
Cancer Sub-Classification / Subtype
CHIC2/ETV6-Mediated Acute Myeloid Leukemia
Definition / Description of Disease
A blood cancer in which the bone marrow makes abnormal myeloblasts due to t(4;12)(q12;p13) resulting in CHIC2-ETV6 gene fusion. CHIC2 is a member of a family of proteins that function in exocytosis. ETV6 is an erythroblast-transformation specific transcription factor. Research has suggested that ectopic expression of the homeobox gene GSH2 located near the breakpoint at 4q12 may be the underlying leukemogenic factor, independent of the presence of fusion transcripts. This translocation is a recurrent but rare finding in patients with acute myeloid leukemia, and a poor response to therapy has been reported.
Synonyms / Terminology
Acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia
Epidemiology / Prevalence
Thirteen cases of CHIC2/ETV6-mediated acute myeloid leukemia have been reported in the literature. All of these cases occurred in adults, and there is no predilection for a particular sex. This translocation has also been reported in 4 cases of acute lymphocytic leukemia, 1 case of myeloid/natural killer cell leukemia and 1 case of chronic myeloid leukemia.
Clinical Features
Fever, fatigue, bruising, bleeding, weight loss, fever, nausea, and vomiting
Sites of Involvement
Peripheral blood and bone marrow
Morphologic Features
Morphologic features have ranged from a dry tap to hypercellular bone marrow with multilineage dysplasia.
Immunophenotype
Myeloblasts have been reported to express dim CD7, CD13, CD34, HLA-DR, CD4, CD34, CD56, and CD33.
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
Chromosomal Rearrangements (Gene Fusions)
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| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| t(4;12)(q12;p13) | 5'CHIC2 / 3'ETV6 | ?der(12) | Rare |
Characteristic Chromosomal Aberrations / Patterns
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Genomic Gain/Loss/LOH
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| Chromosome Number | Gain/Loss/Amp/LOH | Region |
|---|---|---|
| EXAMPLE 8 | EXAMPLE Gain | EXAMPLE chr8:0-1000000 |
| EXAMPLE 7 | EXAMPLE Loss | EXAMPLE chr7:0-1000000 |
Gene Mutations (SNV/INDEL)
One case has been reported with additional mutations including FLT3, NRAS codon 12, MLL-PTD and TP53; however, this was an isolated finding, and no other cases have demonstrated similar results.
| Gene | Mutation | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|---|
| EXAMPLE TP53 | EXAMPLE R273H | EXAMPLE Tumor Suppressor | EXAMPLE LOF | EXAMPLE 20% |
Other Mutations
| Type | Gene/Region/Other |
|---|---|
| Concomitant Mutations | EXAMPLE IDH1 R123H |
| Secondary Mutations | EXAMPLE Trisomy 7 |
| Mutually Exclusive | EXAMPLE EGFR Amplification |
Epigenomics (Methylation)
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Genes and Main Pathways Involved
CHIC2 is a member of a family of proteins that function in exocytosis, and ETV6 is an erythroblast-transformation specific transcription factor. Research has suggested that ectopic expression of the homeobox gene GSH2 located near the breakpoint at 4q11-q12 may be the underlying leukemogenic factor; however, more research is needed to name a definitive pathway.
Diagnostic Testing Methods
Classical cytogenetics, FISH and molecular genetics
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
A poor response to therapy has been reported. There is limited data on prognosis; however, based on the cases reported, median survival is suggested to be about one year.
Familial Forms
No familial forms have been documented.
Other Information
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Links
References
1. Cools J, et al., (1999). Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q21;p13). Blood 94(5):1820-1824, PMID 10477709.
2. Cools J, et al., (2002). Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13). Blood 99(5):1776-1784, PMID 11861295.
3. Huret JL (2002). t(4;12)(q11-q21;p13). Atlas Genet Cytogenet Oncol Haematol 6(2):128-129.
4. Kuchenbauer F, et al., (2005). A rare case of acute myeloid leukemia with a CHIC2-ETV6 fusion gene and multiple other molecular aberrations. Leukemia 19(12):2366-2368, PMID 16224488.
Notes
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