ETV6-ABL1 CML Like Disorder with Complex Translocation Involving Chromosome 9, 12 and 14

Abstract 4438

A rare group of myeloproliferative disorders has been described associated with gene rearrangements producing novel tyrosine kinases other than BCR/ABL.

A rearrangement involving the ETV6 and ABL1 genes, associated with t(9;12)(q34;p13) translocation, has been detected in Ph-negative chronic myeloproliferative disorders and has been demonstrated to have tyrosine kinase activity in signal transduction pathways similar to the BCR/ABL fusion protein. The ETV6 gene is a member of the E26 transformation-specific family (ETS) of transcription factors located at 12p13. It has been implicated in the rearrangement of over 48 different chromosome bands, ultimately playing a role in leukemogenesis. Thus far, only eleven BCRABL1-negative CML patients with a variant ABL1 gene (9q34) rearrangement, involving fusion to ETV6 aka TEL (12p13) have been reported. ETV6-ABL1 rearrangement have also been implicated in other hematologic diseases including 6 acute B lymphoid leukemia, 1 acute T lymphoid leukemia, 3 acute myeloid leukemia, 1 myelodysplastic syndrome, and 3 chronic myeloproliferative disorders.

We present a 62 year old male who sought medical attention for acute coronary syndrome with bone pain and asthenia in May 2011. Physical exam showed a splenomegaly. He was found to have hemoglobin of 9.9g/dL, WBC 90G/L and platelets 105G/L. The peripheral blood differential count revealed 67% segmented neutrophils, 2% eosinophils, 0 basophils, 3% monocyte, 28% immature stages and 5% lymphocytes per 100 white blood cells. Bone marrow biopsy revealed myeloid hyperplasia suggestive of a myeloproliferative disorder. The genetic characteristic of this patient is to present an exceptional chromosomal complex rearrangement according to Pellestor classification, involving 3 chromosomes 9, 14, 12 with five breakpoints: 9q, 12p, 12q, and two different on 14q. More precisely, it probably compounds of a three way translocation t(9;12;14)(q34,p13,q?) associated with a independent translocation between both long arms of chromosomes 12 and 14. FISH analysis using BCR/ABL TC DFusion (Kreatech) shows involvement of ABL1 probe in a translocation with short arm of chromosome 12 and no evidence of rearrangement of BCR gene suggesting the possibility of juxtaposition of ABL1 gene with a gene different than the BCR gene. Moreover whole chromosome 14 painting confirms various involvements of chromosome 14. Molecular biology confirmed the suspected ETV6-ABL1 fusion gene and allows us to follow minimal residual disease. It should be noted that a t(9;12;14)(q34;p13;q22) has already been described as a variant of the t(9;12)(q34;p13) with complex insertions of ETV6 into ABL1. Other chromosome than the 14 has known to be implicated in t(9;12) variant as chromosome 17.

First, he was treated with imatinib with progression despite the addition of hydroxyurea. Treatment was switched at 3 months for dasatinib. At 3 months, ETV6-ABL1/ABL1 is 0.32% and at 6 months he obtains a Major Molecular Response (defined as MRD under 0.1% like in BCR-ABL measurement).

In conclusion, we present a new case of ETV6-ABL1 myeloproliferative disorder due to complex rearragement which experiments good response to dasatinib suggesting that second generation TKI are a good option for treatment of such disease.