Adrenomedullin Receptor Calcrl Drives Drug Resistance of Leukemic Stem Cells in Acute Myeloid Leukemia

Abstract

After intensive chemotherapy, the emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein, we first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients compared to normal cells and preferentially in the immature CD34+CD38- compartment. Then, we demonstrated its role in the maintenance of leukemic stem cell function in vivo (Figure A). Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. Accordingly, we showed that ADM-CALCRL axis drove BCL2 pathway, cell cycle and DNA integrity in E2F1-dependent manner, and high OxPHOS status that we previously described as a feature of minimal residual disease after chemotherapy (Farge et al., 2017). Moreover, CALCRL expression predicted the response to chemotherapy in vivo in mice (n=10 Patient Derived Xenografts; Figure B) and in patients. Further, using the combination of limiting dilution assays, single cell RNA-seq analysis of primary AML samples at diagnosis and relapse and before and after transplantation in NSG mice, we revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL gene signature (Figure C-D). All of these data highlight the critical role of CALCRL in stem cell function and metabolism. They also identify this receptor as a new druggable marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.