Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation
Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest 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 two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN.
- 16 samples
- DAC: EGAC00000000011
- RS DUO:0000012 (version: 2021-02-23)research specific restrictionsThis data use modifier indicates that use is limited to studies of a certain research type.
- RU DUO:0000014 (version: 2019-01-07)research use onlyThis data use limitation indicates that use is limited to research purposes (e.g., does not include its use in clinical care).
- TS DUO:0000025 (version: 2021-02-23)time limit on useThis data use modifier indicates that use is approved for a specific number of months.
- PS DUO:0000027 (version: 2021-02-23)project specific restrictionThis data use modifier indicates that use is limited to use within an approved project.
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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.
| Study ID | Study Title | Study Type |
|---|---|---|
| EGAS00001004113 | Other |
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