Acute myeloid leukemia with t(4;12)(q12;p13), CHIC2-ETV6

Primary Author(s)*

Paige Woodham, Daynna J. Wolff

Cancer Category/Type

Acute Myeloid Leukemia

Cancer Sub-Classification / Subtype

AML with t(4;12),CHIC2-ETV6

Definition / Description of Disease

A blood cancer in which the bone marrow makes abnormal myeloblasts due to t(4;12)(q12;p13) 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 translocation 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

13 cases of CHIC2/ETV6-Mediated Acute Myeloid Leukemia have been reported in the literature. All of these cases have been reported 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

Patients typically present with B-symptoms: fever, fatigue, bruising, bleeding, weight loss, fever, nausea, vomiting

Sites of Involvement

Peripheral blood, 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.

Chromosomal Rearrangements (Gene Fusions)

Put your text here and/or fill in the table

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(4;12)(q12;p13)	5'CHIC2 / 3'ETV6	? der(12)	rare

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 findings.

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 RNA sequencing for fusion

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.

References

Cools, J., Bilhou-Nabera, C., et al. “Fusion of a Novel Gene, BTL, to ETV6 in Acute Myeloid Leukemias with a t(4;12)(q11-q21;p13)”. Blood. 1999 Sep 1;94(5): 1820-4. PMID: 10477709

Cools, J., Mentens, N., et al. “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. 2002 Mar 1;99(5): 1776-84. PMID: 11861295

Huret JL. t(4;12)(q11-q21;p13). Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2):128-129.

Kuchenbauer F., Schoch C., et al. “A Rare Case of Acute Myeloid Leukemia with a CHIC2-ETV6 Fusiongen and Multiple other Molecular Aberrations”. Leukemia. 2005 Dec; 19(12): 2366-8. PMID: 16224488 DOI:10.1038/sj.leu.2403957