Abstract
Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
Highlights
Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells
Differentiation therapy has proven effective in acute promyelocytic leukemia (APL), an AML subtype driven by the PML-RARA fusion oncoprotein[2]
The mouse AML246 leukemia model is driven by knockdown of PU.[1], a myeloid transcription factor directly inhibited by several recurrent AML driver proteins including PML-RARA, AML1-ETO, and NPM1c
Summary
AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Using genetic approaches we show that restricting therapyinduced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure These results indicate that relapse can originate from therapyresistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome. All-trans retinoic acid (ATRA) therapy triggers PML-RARA degradation and en masse leukemia maturation, resulting in acute AML-derived leukocytosis within 1–3 weeks and an associated differentiation syndrome in ~25% of patients[3,4]. Clinical response to mutant IDH1/2 inhibitors is associated with AML maturation that yields functional IDH-mutant neutrophils[19,20,21,22], with differentiation syndrome in ~10% of these patients[22,23]. Almost all patients treated with mutant IDH1/2 inhibitors eventually relapse, even after complete remission[20,22]
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