Abstract
Acute myeloid leukemia (AML) has high mortality rates, perhaps reflecting a lack of understanding of the molecular diversity in various subtypes and a lack of known actionable targets. There are currently 12 open clinical trials for AML using combination therapeutic modalities including all-trans retinoic acid (RA). Mutant nucleophosmin-1, proposed as a possible marker for RA response, is the criterion for recruiting patients in three active RA phase 3 clinical trials. We tested the ability of RA alone or in combination with either bosutinib (B) or 6-formylindolo(3,2-b) carbazole (F) to induce conversion of 12 de novo AML samples toward a more differentiated phenotype. We assessed levels of expression of cell surface markers associated with differentiation, aldehyde dehydrogenase activity, and glucose uptake activity. Colony formation capacity was reduced with the combined treatment of RA and B or F, and correlated with modulation of a c-Cbl/Lyn/c-Raf-centered signalsome. Combination treatment was in most cases more effective than RA alone. Based on their responses to the treatments, some primary leukemic samples cluster closer to HL-60 cells than to other primary samples, suggesting that they may represent a hitherto undefined AML subtype that is potentially responsive to RA in a combination differentiation therapy.
Highlights
Acute myeloid leukemia (AML) is the most frequently occurring adult leukemia
We report four main conclusions. 1. c-Cbl used as a prognostic indicator with NPM1 results in better disease-free survival (DFS) stratification than NPM1 alone; in particular, AML with mut-NPM1 and low c-Cbl expression performed better than high c-Cbl. 2
We previously reported a signalsome that generates signaling seminal to retinoic acid (RA)-induced differentiation in a well-studied patient derived non-acute promyelocytic leukemia (non-APL) AML cell line, HL-60, that responds to RA and differentiates with cell cycle arrest
Summary
Acute myeloid leukemia (AML) is the most frequently occurring adult leukemia (comprising about 30% of new leukemias). There are currently 12 open clinical trials for non-acute promyelocytic leukemia (non-APL) AML using combination therapeutic modalities including retinoic acid (RA), a very successful differentiating agent in the case of APL Those include NCT01237808, NCT00893399, NCT03031249, phase-3 clinical trials for adult patients with AML and nucleophosmin (NPM1) mutation. Given the high heterogeneity of AML pathology, improving AML patient survival rates depends on characterizing the networks that link genetic defects to molecular signaling and molecular signaling to cellular functional outcomes. We look at the correlation of NPM1 and markers of differentiation status Using this data to select a limited number of samples that embodied a diversity of traits, we tested their response to RA or RA plus a small molecule targeting AhR, measuring their colony forming/ growth capacity in methylcellulose. We ergo put forth the conjecture that there is an AML subtype that can respond to RA in combination with other agents, and it is captured in vitro by the HL-60 cell line
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