Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

Nat Commun. 2021 Jan 18;12(1):422. doi: 10.1038/s41467-020-20717-9.

Abstract

Drug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair, and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcitonin Receptor-Like Protein / genetics
  • Calcitonin Receptor-Like Protein / metabolism*
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / prevention & control
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Oxidative Phosphorylation / drug effects
  • Primary Cell Culture
  • Prognosis
  • Xenograft Model Antitumor Assays

Substances

  • ADM protein, human
  • Antineoplastic Agents
  • CALCRL protein, human
  • Calcitonin Receptor-Like Protein
  • Adrenomedullin
  • Calcitonin Gene-Related Peptide