A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes

Jing Fang, Xiaona Liu, Lyndsey Bolanos, Brenden Barker, Carmela Rigolino, Agostino Cortelezzi, Esther N. Oliva, Maria Cuzzola, H. Leighton Grimes, Celia Fontanillo, Kakajan Komurov, Kyle Macbeth, Daniel T. Starczynowski

Research output: Contribution to journalArticle

Abstract

Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.

Original languageEnglish
Pages (from-to)727-734
Number of pages8
JournalNature Medicine
Volume22
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Calpain
Myelodysplastic Syndromes
Calcium
Acute Myeloid Leukemia
Genes
Zinc Fingers
Myeloid Cells
Zinc
lenalidomide
Chemical activation
Chromosome Deletion
Gene Regulatory Networks
Cytotoxicity
Chromosomes
G-Protein-Coupled Receptors
RNA Interference
Metabolism
Clone Cells
Cells
RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. / Fang, Jing; Liu, Xiaona; Bolanos, Lyndsey; Barker, Brenden; Rigolino, Carmela; Cortelezzi, Agostino; Oliva, Esther N.; Cuzzola, Maria; Grimes, H. Leighton; Fontanillo, Celia; Komurov, Kakajan; Macbeth, Kyle; Starczynowski, Daniel T.

In: Nature Medicine, Vol. 22, No. 7, 01.07.2016, p. 727-734.

Research output: Contribution to journalArticle

Fang, J, Liu, X, Bolanos, L, Barker, B, Rigolino, C, Cortelezzi, A, Oliva, EN, Cuzzola, M, Grimes, HL, Fontanillo, C, Komurov, K, Macbeth, K & Starczynowski, DT 2016, 'A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes', Nature Medicine, vol. 22, no. 7, pp. 727-734. https://doi.org/10.1038/nm.4127
Fang, Jing ; Liu, Xiaona ; Bolanos, Lyndsey ; Barker, Brenden ; Rigolino, Carmela ; Cortelezzi, Agostino ; Oliva, Esther N. ; Cuzzola, Maria ; Grimes, H. Leighton ; Fontanillo, Celia ; Komurov, Kakajan ; Macbeth, Kyle ; Starczynowski, Daniel T. / A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. In: Nature Medicine. 2016 ; Vol. 22, No. 7. pp. 727-734.
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