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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging [STAT5B.sup.N642H] driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying [STAT5B.sup.N642H]., Introduction Acute lymphoblastic leukemia (ALL) is subdivided into B and T cell acute lymphoblastic leukemia (T-ALL), of which T-ALL represents up to 15% of pediatric and 25% of adult ALL [...]

IL-17-producing [ROR[gamma]t.sup.+] [gamma][delta] T cells ([gamma][delta]T17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that [gamma][delta]T17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-[gamma] in a STAT3- and retinoic acid-dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in [gamma][delta]T17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting [gamma][delta]T17 cell expansion and downregulating gut-associated T- bet. In contrast, STAT5B preferentially expanded IFN-[gamma]producing yd populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking [gamma][delta]T17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic [gamma][delta]T17 development and tissue-specific imprinting, which is essential for infection and autoimmunity., Introduction IL-17-producing [gamma][delta] T cells ([gamma][delta]T17 cells) are one of the major type 3 innate lymphocytes in the mouse, occupying the skin and most mucosal surfaces as well as secondary [...]

STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5[B.sup.N642H] in the hematopoietic compartment. While STAT5B -expressing mice lacked a hematopoietic phenotype, the STAT5[B.sup.N642H]-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable [CD8.sup.+] lymphoma or leukemia, indicating that the STAT5[B.sup.N642H] mutation drives cancer development. Persistent and enhanced levels of STAT5[B.sup.N642H] tyrosine phosphorylation in transformed [CD8.sup.+] T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5[B.sup.N642H]-expressing [CD8.sup.+] T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5[B.sup.N642H] mutation who respond poorly to conventional chemotherapy., Introduction The 2 signal transducer and activator of transcription 5 proteins, STAT5A and STAT5B, encoded by 2 different genes with 89% DNA sequence homology, are downstream targets of cytokines and [...]