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Background:T-cell leukemias and lymphomas (TL&Ls) are rare when compared with other hematologic malignancies, and pose a challenge for clinical management. TL&Ls are characteristically resistant to chemotherapeutic regimens used to treat other hematologic malignancies (PMID 17369126, 22649104, 25042790). Recently, activating JAK1and JAK3mutations have been described in a subset of mature TL&Ls including adult T-cell leukemias/lymphoma (ATLL), NK/T-cell lymphoma, and T-cell prolymphocytic leukemia (T-PLL). We used a comprehensive hybrid capture-based sequencing assay to identify genomic alterations that might suggest benefit from targeted therapy.

Hematopoietically expressed homeobox(Hhex) is a T-cell oncogene. It is frequently deregulated in murine retroviral insertional mutagenesis screens and its enforced expression induces T-cell leukemia in bone marrow transduction and transplantation experiments. We discovered that HHEXis a direct transcriptional target of an LIM domain Only-2 (LMO2)-associated protein complex. HHEXclusters with LMO2-overexpressing T-ALLs and is especially overexpressed in Early T-cell Precursor (ETP) – ALL where it is a direct transcriptional target of LMO2. To further understand Hhex's function, we induced a conditional knockout in floxed Hhexmice with the Vav-iCretransgene. Mice were viable and showed normal blood cell counts with highly efficient deletion of Hhexin all hematopoietic tissues. Thymocytes from conditional knockouts showed a normal pattern of development. Most impressively, Hhexconditional knockout markedly prolonged the latency of T-ALL onset in CD2-Lmo2transgenic mice (figure 1). Hhexconditional knockouts (HhexcKOs) also had a significant decrease in mature B cells in the spleen and bone marrow. Interestingly, hematopoietic stem and progenitor cells plated on OP9-GFP or OP9-DL1 stromal cells showed proliferative defects and incomplete differentiation towards both B and T lineage. Also under stress conditions such as sublethal irradiation and competitive bone marrow transplants, Hhex conditional knockouts show a marked defect in both B and T lineages but an increase in early progenitor populations. Our experiments show that Hhexis a critical transcription factor in lymphoid development and in LMO2-induced T-ALL.Figure 1Hhexconditional knockout markedly prolonged the latency of T-ALL onset in CD2-Lmo2transgenic miceFigure 1. Hhex conditional knockout markedly prolonged the latency of T-ALL onset in CD2-Lmo2 transgenic mice