ETV6Gene Rearrangements in Hematopoietic Malignant Disorders

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Abstract
Chromosomal abnormalities involving the short arm of chromosome 12 have been frequently observed in a broad spectrum of hematological malignancies. Recently, a gene located in this chromosomal region and implicated in leukemogenesis was identified. The gene, called ETV6 (previously known as TEL) is a new member of the ETS family, a group of genes thought to act as transcriptional activators. The gene spans 240 kb and consists of eight exons coding for a helix-loop-helix (HLH) and a DNA-binding domain. ETV6 was originally identified in a t(5;12)(q33;p13) occurring in a chronic myelomonocytic leukemia (CMML). Recent reports, however, show its involvement in a growing number of translocations associated with myeloid as well as lymphoid leukemias. At the molecular level fusions of ETV6 with PDGFRB (5q33), ABL (9q34), MN1 (22q11) and AML1(21q22) have already been identified. Analysis of these chimeric proteins indicates that distinct domains of ETV6 can be involved in different fusion products; thus ETV6 can provide transcriptional and dimerization properties for partner genes, or the gene itself can act as an altered transcriptional factor. At least two clinico-pathological entities associated with ETV6 rearrangements have emerged as distinct disorders. The first one is a chronic myeloid malignancy characterized by t(5; 12)(q33;p 13), monocytosis and/or eosinophilia. The second entity is a type of childhood acute lymphoblastic leukemia (ALL) hallmarked by t(12;21)(p13;q22), and is shown to be the most frequent but cytogenetically largely undetectable chromosomal anomaly in childhood ALL. SUMMARY ETV6, a leukemia associated gene located on 12p 13, is involved in different chromosomal translocations found in myeloid and lymphoid malignancies, resulting in the formation of fusion proteins with oncogenic potential. Contribution of distinct domains of this gene, namely HLH and DNA-binding motif, in chimeric products suggests different mechanisms of ETV6 involvement in leukemogenesis. Type of ETV6 rearrangement does not correlate with the lineage of neoplastic cells. Although the mechanisms of transformation by ETV6-related aberrant proteins are not known, the possibility exists that at least some of them, like ETV6-PDGFRB, ETV6-ABL and MN1-ETV6 are components of the RAS signal transduction pathway. Functional analysis of these fusion proteins will therefore be important in elucidating the role of ETV6 in the oncogenic process. Among hematopoietic disorders with ETV6 rearrangements at least two clinico-pathological entities are distinguished. The first is a group of chronic myeloid disorders characterized by t(5;12). The second represents childhood B-cell ALL with a t(12;21), and constitutes the most frequent abnormality in this subtype of leukemia. The clinical significance of other more sporadic ETV6 rearrangement observed in acute lymphoid or myeloid leukemias thus far could not be established.