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Martinez-Høyer, Sergio; Deng, Yu; Parker, Jeremy; Jiang, Jihong; Mo, Angela; Docking, T Roderick; Gharaee, Nadia; Li, Jenny; Umlandt, Patricia; Fuller, Megan; Jädersten, Martin; Kulasekararaj, Austin; Malcovati, Luca; List, Alan F; Hellström-Lindberg, Eva; Platzbecker, Uwe; Karsan, Aly
Nature cell biology, 05/2020, Letnik: 22, Številka: 5Journal Article
Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS) . Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients . 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 . 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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