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Leukemia relapse is widely assumed to arise from a malignant clone. On page 114, Landberg et al. demonstrate that IDH1-mutant preleukemic stem/progenitor cells (pHSPC) resist IDH1-targeted therapies, lending support to the idea that targeted-therapy resistance may originate from a premalignant reservoir. Exploring metabolic dependencies of human pHSPCs, this study identifies small molecule inhibitors of oxidative phosphorylation as safe for normal hematopoiesis (blue colonies in the artwork) and effective against leukemic and preleukemic IDH1-mutant HSPCs (depicted as green and blue colonies). The findings suggest that eradicating premalignant leukemia-initiating reservoirs is possible but may require therapies distinct from those targeting malignant cells. For details, please see the article on p. 114 and the accompanying commentary by Steensma on pp. 83. - PDF Icon PDF LinkTable of Contents
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Research Briefs
Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia
Data in acute myeloid leukemia cell lines and computational models demonstrate that synergy in drug combinations promotes the development of resistance and increases the fitness benefit conferred when resistance develops.
Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma
A simple model is used to stratify patients following CD19 targeted CAR T-cell therapy for large B-cell lymphoma using readily available laboratory tests. High baseline CRP and ferritin identifies patients with worse toxicity and clinical response.
Research Article
IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation
Preleukemic hematopoietic stem cells with an IDH1-mutation are epigenetically, transcriptomically, and metabolically distinct from wild-type hematopoietic stem cells and IDH2-mutant cells and can be specifically targeted using complex I inhibitors.
Correction
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