Genetic characterization and therapeutic targeting of MYC rearranged T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological tumor that arises from T-cell precursor cells, is often characterized by T cell receptor (TCR) translocations that drive aberrant activation of specific proto-oncogenes. Here, we performed a detailed molecular genetic characterization of a rare but aggressive genetic subtype of human T-ALL, ie. patients that present with a t(8;14)(q24;q11) translocation, in which high MYC levels are driven by enhancer elements of the TCR a/d locus (TCRAD-MYC). Notably, analysis of an extensive series of primary leukemia samples confirmed that TCRAD-MYC translocation positive T-ALLs represent a NOTCH1 independent subtype of T-cell leukemia characterized by aberrant activation of the TAL1 and/or LMO2 transcription factor oncogenes and frequent activation of the PI3K/AKT signaling pathway. From a therapeutic perspective, in vivo drug treatment experiments using primary patient derived xenografts revealed that TCRAD-MYC positive T-ALLs are sensitive to BET bromodomain inhibition, providing a rationale to develop BRD4 inhibitors as an adjuvant therapy for this rare, but genetically well-defined, high-risk subtype of human leukemia. Overall design: We performed H3K27ac chromatin immunoprecipitation (ChIP) sequencing analysis on the t(8;14)(q24;q11) positive MOLT16 cells to study the enhancer landscape in proximity of the TCRAD locus, which is involved in TCRAD-MYC translocation in a rare T-ALL subgroup.