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

  • Quantitative Biology Unit
January 18, 2021 By:
  • Larrue C
  • Guiraud N
  • Mouchel PL
  • Dubois M
  • Farge T
  • Gotanegre M
  • Bosc C
  • Saland E
  • Nicolau-Travers ML
  • Sabatier M
  • Serhan N
  • Sahal A
  • Boet E
  • Mouche S
  • Heydt Q
  • Aroua N
  • Stuani L
  • Kaoma T
  • Angenendt L
  • Mikesch JH
  • Schliemann C
  • Vergez F
  • Tamburini J
  • Recher C
  • Sarry JE.

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.

2021 Jan. Nat Commun.12(1):422.
Other information