The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. IntroductionThe Ataxia Telangiectasia Mutated (ATM) tumor suppressor gene encodes a principal DNA damage-signaling protein, and cells with ATM dysfunction exhibit increased radiosensitivity, loss of cellcycle checkpoints, and p53 dysfunction. [1][2][3][4][5] In addition to the impaired apoptotic response, the cellular phenotype of these cells can be attributed to subtle but significant defects in both major types of DNA double strand break (DSB) repair: error-prone non-homologous end joining (NHEJ), preferentially employed in the gap 1 (G1) phase of the cell cycle, and error-free homologous recombination (HR) repair, restricted to synthesis/gap 2/mitosis (S/G2/M) phases of the cell cycle. 6-11 After DNA damage, ATM mutant cells consequently exhibit prolonged DNA DSBs and abnormal retention of DNA proteins at the sites of DNA DSB observed as intra-nuclear foci. [6][7][8][9][10][11] Inactivation of ATM is a frequent event in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (CLL), [12][13][14] T-prolymphocytic leukemia (T-PLL) 15,16 and mantle cell leukemia (MCL). 17 CLL is the most common leukemia in western countries. While many patients do not require therapeutic intervention, those with progressive CLL have a poor overall outcome, and survival is greatly impaired by the presence of genetic abnormalities such as 11q deletions/ATM mutations and 17p deletions/TP53 mutations. [18][19][20][21][22][23] The less-frequent malignancies, T-PLL and MCL, also commonly harbor 11q deletions and ATM mutations, 15-17 which may contribute to their dismal clinical responses. Progressive lymphoid malignancies are currently treated with combinations of nucleoside analogues and alkylating agents, which typically exert their effect through the generation of DNA damage and subsequent induction of an ATM/p53-dependent apoptotic pathway. 24 Consistent with this mechanism, ATM mutant CLL cells exhibit resistance to fludarabine-induced apoptosis in vitro. 21 The adverse impact of ATM inactivation on clinical responses of this subtype to current therapies may be evident at several levels: The presence of pathogenic ATM mutations causes rapid clonal expansion of 11qdel subclones 21 and significantly reduces overall survival 21 as well as progression-free survival in patients treated in the United Kingdom CLL4 trial (A.S., V.W., D.O., G.P., A.M.R.T., T.S., manuscript in preparation). Recent developments in front-line regimens by the addition of rituximab to fludarabine and cyclophosphamide (FCR) and second-line alemtuzumab and flavopiridol [22][23][24][25][26][27] has resulted in some clinical benefits for 11q del CLL 24 as well as other progressive lymphomas. 26,27 Despite these improvements, immunosuppression and toxicity ...
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Key Points• Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. (Blood. 2015;125(15):2386-2396
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