Cited by 42Acute Myeloid Leukemia ResearchProtein Degradation and InhibitorsRetinoids in leukemia and cellular processes

Loss of lenalidomide-induced megakaryocytic differentiation leads to therapy resistance in del(5q) myelodysplastic syndrome

Martinez-Høyer, Sergio, Deng, Yu, Parker, Jeremy, Jiang, Jihong, Mo, Angela, Docking, T. Roderick, Gharaee, Nadia, Li, Jenny +9 more·2020·Nature Cell Biology

Abstract

Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS)1. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant 2 within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients 3. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation 4,5. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1-GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.

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Crossref · 10.1038/s41556-020-0497-9

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  • Co-occurring TP53 mutations probably explain why patients with del(5q) in combination with a complex karyotype or in the setting of AML do not respond to lenalidomide.

    “Co-occurring TP53 mutations probably also explain why patients with del(5q) in combination with a complex karyotype or in the setting of AML do not respond to lenalidomide99.”

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Authors
Martinez-Høyer, S., Deng, Y., Parker, J., Jiang, J., Mo, A., Docking, T. R., Gharaee, N., Li, J., Umlandt, P., Fuller, M., Jädersten, M., Kulasekararaj, A., Malcovati, L., List, A. F., Hellström-Lindberg, E., Platzbecker, U., & Karsan, A.
Affiliations
  • University of British Columbia (CA)
  • Canada's Michael Smith Genome Sciences Centre (CA)
  • Karolinska University Hospital (SE)
  • King's College London (GB)
  • University of Pavia (IT)
  • Moffitt Cancer Center (US)
  • University Hospital Leipzig (DE)
Corresponding author
Karsan, Aly
Venue
Nature Cell Biology
Published
2020-04-06
Volume
22
Issue
5
Pages
526-533
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
OpenAlex
W3014527633
Cited by
42
References
37
Citations by year
2026: 1 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 6
FWCI
4.58
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Associazione Italiana per la Ricerca sul Cancro (21267)
  • Leukemia and Lymphoma Society of Canada (515899)
  • Terry Fox Research Institute (1074)
  • Gouvernement du Canada | Canadian Institutes of Health Research (PJT-166051, PJT-162131)
  • Genome British Columbia (121AML)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
lenalidomide resistance, del(5q) myelodysplastic syndrome, megakaryopoiesis, TP53 mutation, RUNX1 mutation, GATA2, cereblon, calpain, CSNK1A1, treatment resistance, prognostic factors
MeSH terms
Lenalidomide, Cell Differentiation, Cell Line, Chromosomes, Human, Pair 5, Humans, Megakaryocytes, Mutation, Myelodysplastic Syndromes, Down-Regulation, Tumor Suppressor Protein p53, Core Binding Factor Alpha 2 Subunit, GATA2 Transcription Factor, HEK293 Cells

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