FCM significantly improves the sensitivity of CC for the identification of leptomeningeal disease in aggressive B-NHL at higher risk of CNS disease, particularly in paucicellular samples.

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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...

Loss of function mutations and deletions encompassing the PHF6 gene are present in about 20% of T-cell acute lymphoblastic leukemias. Here we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AML). Genetic lesions in PHF6 found in AML are frameshift and nonsense mutations distributed through the gene or point mutations involving the second PHD-like domain of the protein. As in the case of T-ALL, where PHF6 alterations are found almost exclusively in males, mutations in PHF6 were 7 times more prevalent in males than in females with AML. Overall these results identify PHF6 as a tumor suppressor mutated in AML and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors.