Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wildtype populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.acute lymphoblastic leukemia | relapsed leukemia | chemotherapy resistance | genome sequencing A cute lymphoblastic leukemia (ALL) is the most common malignancy in children (1-4). Current therapy of pediatric newly diagnosed ALL includes initial clearance of leukemic lymphoblasts with cytotoxic drugs and glucocorticoids followed by delivery of chemotherapy to the central nervous system and a prolonged lower intensity maintenance treatment phase aimed at securing long-term remission by reducing the rates of leukemia relapse (3). Altogether 95% of pediatric ALL patients achieve a complete hematologic remission during induction and 80% of them remain leukemia free (5). However, the prognosis of patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor, with cure rates of less than 40% (6, 7). Several mechanisms have been implicated as drivers of leukemia relapse, including the presence of rare quiescent and intrinsically chemoresistant leukemia stem cells with increased self-renewal capacity (8), protection from chemotherapy by safe-haven microenvironment niches (9, 10), and selection of secondary genetic alterations promoting chemotherapy resistance in leukemic lymphoblasts (11)(12)(13). In this regard, early studies described the presence of tumor protein p53 (TP53) mutations in relapsed ALL, supporting a role for escape from genotoxic stress in leukemia progression (14). Similarly, lo...

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL.peripheral T-cell lymphoma | VAV1 | mutation | gene fusion P eripheral T-cell lymphomas (PTCLs) are malignant and highly aggressive hematologic tumors arising from mature postthymic T cells (1). The diagnosis of PTCL includes diverse lymphoma subgroups, altogether accounting for about 15% of all non-Hodgkin lymphomas (2, 3). Despite much effort in developing reliable diagnostic markers, the diagnosis of PTCLs is challenging, and 20 to 30% of cases are diagnosed as PTCL-NOS (not otherwise specified). This heterogeneous and poorly defined group constitutes one of the most aggressive forms of non-Hodgkin lymphoma, in which limited response to intensified chemotherapy and high relapse rates result in a dismal 5-y overall survival rate of 20 to 30% (4, 5). Moreover, a paucity of information on driver oncogenes activated in PTCL-NOS hampers the development of targeted therapies in this aggressive lymphoma subgroup.The VAV1 protooncogene encodes a guanine nucleotide exchange factor (GEF) and adaptor protein with crucial signaling roles in protein tyrosine kinase-regulated pathways (6). Structurally, VAV1 contains a calponin homology domain and an acidic domain in the N terminus followed by a GEF catalytic active core consisting of a central Dbl homology domain, pleckstrin homology domain, and C1 domain (6). Finally, the C-terminal region of VAV1 contains three Src homology domains in an SH3-SH2-SH3 arrangement (6). The GEF activity of VAV1 stimulates the transition of RAC1 and RHOA small GTPases from their inactive (GDP-bound) to the active (GTP-bound) configuration (6-8). In addition, the adaptor function of VAV1 mediates activation of the nuclear factor of activated T cells (NFAT) in synergy with signals from antigenic receptors in lymphoid cells (6,(8)(9)(10)(11)(12)(13). In basal conditions, unphosphorylated VAV1 adopts an inactive closed configuration in which the N-terminal calponin homology and acidic domains and