TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA

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A novel variety of stem-cell leukemia/lymphoma involving T-cell, B-cell, and myeloid lineages has been described in the past three years. Most patients present with peripheral lymphadenopathy, and lymph node biopsies typically reveal T-cell lymphoblastic lymphoma. Concomitant bone marrow biopsy, on the other hand, generally demonstrates myeloid hyperplasia with pronounced eosinophilia. The lymphoma responds well to therapy, but most patients progress to a full-blown, rapidly fatal, acute myelogenous leukemia. It is notable that patients with this syndrome have balanced reciprocal translocation, involving chromosome bands 8p11 and 13q11-12, both in the lymphomatous peripheral nodes and in the myeloproliferative bone marrow cells. This observation suggests that translocation (8;13) is a critical oncogenetic event in a pluripotential cell capable of both myeloid and lymphoid differentiation. We have mapped the translocation (8;13) breakpoints using molecular cytogenetic approaches and have localized the 8p breakpoint to a 70 kb bacterial artificial chromosome (BAC) clone. Our preliminary BAC cDNA screening studies have implicated FGFRI as one candidate gene in the translocation (;13). We hypothesize that a gene at the translocation 8p breakpoint is oncogenic and is activated by juxtaposition with an oncogene on the chromosome 13 long arm. We will answer these hypotheses by evaluating t(813) lymphomas for FGFRI genomic rearrangements and aberrant transcripts. If those studies are negative, we will continue to screen selected cDNA libraries for expressed sequences mapping to the 8p translocation breakpoint region. Candidate oncogenes will be identified by sequence analysis and will be used as probes in Southern and Northern blots of t(8;13) lymphoma cells cDNAs detecting rearranged fragments on Southern and/or Northern blots will be used as anchors to identify the corresponding oncogene on chromosome 13, and full-length cDNAs will be isolated for both genes. Biologic role of the t(8;13) oncoproteins will be evaluated - both in physiologic hematopoiesis and in leukemogenesis - through in vitro and in vivo functional analysis.