EVI1 activation in blast crisis CML due to juxtaposition to the rare 17q22 partner region as part of a 4-way variant translocation t(9;22)

Dual-colour Fluorescence In Situ Hybridisation was performed to unravel the different cytogenetic aberrations. Expression levels of EVI1 and BCR/ABL1 were investigated using real-time quantitative RT-PCR.In this paper we identified a patient with a complex 4-way t(3;9;17;22) which, in addition to BCR/ABL1 gene fusion, also resulted in EVI1 rearrangement and overexpression.This report illustrates how a variant t(9;22) translocation can specifically target a second oncogene most likely contributing to the more aggressive phenotype of the disease. Molecular analysis of such variants is thus warranted to understand the phenotypic consequences and to open the way for combined molecular therapies in order to tackle the secondary oncogenic effect which is unresponsive to imatinib treatment.Chronic myeloid leukemia (CML) has a typical indolent chronic phase that may last several years but will ultimately progress into acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL). The typical associated translocation t(9;22)(q34;q11), leading to the BCR/ABL1 fusion gene and constitutive activation of the ABL1 tyrosine kinase on 9q34, is considered to be the initial transforming event [1]. Instead of the classical t(9;22) translocation, cryptic and variant translocations occur in about 5 to 10 % of all CML cases. CML in blast crisis is often accompanied by the presence of additional chromosome aberrations [2]. Amongst those, activation of the EVI1 gene has been reported in a small percentage of patients [3]. Ectopic expression of the EVI1 gene is usually due to recurrent 3q26 translocations such as the t(3;21)(q26;q22) (AML1/EVI1) and the inv(3;3)(q21q26). Transcriptional activation of EVI1 can also occur in the absence of genomic rearrangement at this locus [4]. In general, EVI1 upregulation confers a poor prognosis in hematological malignancies [5].In this study, we describe how the molecular characterization of the translocation breakpoints of a variant t(9;22) in a patien