3128 - Characterizing the Role of TLX1 in T-Cell Acute Lymphoblastic Leukemia

Abstract

T-cell Acute Lymphoblastic Leukemias (T-ALLs) are aggressive hematological tumors that result from malignant transformation of T cell progenitors. A major subtype of T-ALL, representing approximately 20% of all cases, is characterized by aberrant expression of the homeobox family transcription factor TLX1 (also called HOX11). TLX1 has no known function in the T cell lineage, and its physiological expression is normally restricted to embryonic development. However, TLX1 is aberrantly expressed in leukemic T-cells. Importantly, the leukemogenic role of TLX1 has been previously demonstrated through forced expression of TLX1 in a transgenic mouse model that developed clonal T cell leukemia. Furthermore, TLX1 is required for leukemic maintenance since its knockdown in T-ALL leads to massive apoptosis of leukemic cells. However, the precise mechanisms through which TLX1 alters gene expression in leukemia is largely unknown. To address this question, I performed immunoprecipitation followed by mass spectrometry to identify cofactors that interact with TLX1 in T-ALL nuclear extracts. These results reveal several novel TLX1-interacting proteins, including chromatin remodelling and histone modifying complexes, suggesting epigenetic mechanisms of gene regulation. Further characterization of these cofactors by chromatin immunoprecipitation is underway to determine their recruitment to TLX1 target genes in T-ALL. Completion of these experiments is expected to provide new insight into the mechanism of TLX1-mediated leukemia.