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Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses., Competing Interests: Declaration of interests A.M. is an employee of Lonza Group AG, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Post-transcriptional RNA modifications determine RNA fate by influencing numerous processes such as translation, decay and localization. One of the most abundant RNA modifications is N 6 -methyladenoside (m 6 A), which has been shown to be important in healthy as well as malignant hematopoiesis. Several proteins representing key players in m 6 A RNA biology, such as m 6 A writers, erasers and readers, were recently reported to be essential for hematopoietic stem cell (HSC) function. In leukemia, expression of m 6 A regulators has been shown to be increased, opening up potential opportunities for therapeutic exploitation by targeting them in blood malignancies. These recent discoveries were the focus of the Fall 2021 International Society for Experimental Hematology New Investigators webinar. We review here the latest findings in the field of mRNA modifications in normal and malignant hematopoiesis and how this might open up novel therapeutic options., Competing Interests: Conflict of interest disclosure The authors declare no competing interests., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)