Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes
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Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan-Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.
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Mutations in PLCγ2 (Q548R), along with PIK3CD (D133E) and AKT3 (D280G), were implicated in myelodysplastic syndrome progression after Azacitidine/Lenalidomide treatment in patients who became refractory or failed to respond.
“Mutations in the PLCγ2 (Q548R) gene, along with PIK3CD (D133E) and AKT3 (D280G), were implicated in myelodysplastic syndrome progression after the chemotherapeutic combination treatment of Azacitidine/Lenalidomide in the cohort of patients who were either first to become refractory to therapy or failed entirely to respond to therapy (139).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [139]
These mutations also were noted to correlate with shorter overall survival and duration of response to treatment.
“These mutations also were noted to correlate with shorter overall survival and duration of response to treatment (139).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [139]
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- Authors
- Follo, M. Y., Pellagatti, A., Armstrong, R. N., Ratti, S., Mongiorgi, S., De Fanti, S., Bochicchio, M. T., Russo, D., Gobbi, M., Miglino, M., Parisi, S., Martinelli, G., Cavo, M., Luiselli, D., McCubrey, J. A., Suh, P.-G., Manzoli, L., Boultwood, J., Finelli, C., & Cocco, L.
- Affiliations
- University of Bologna (IT)
- University of Oxford (GB)
- University of Brescia (IT)
- University of Genoa (IT)
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
- East Carolina University (US)
- Ulsan National Institute of Science and Technology (KR)
- Corresponding author
- Follo, Matilde Y.
- Cocco, Lucio
- ORCID
- Venue
- Leukemia
- Published
- 2019-02-20
- Volume
- 33
- Issue
- 9
- Pages
- 2276-2290
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC6733710
- OpenAlex
- W2917631884
- Cited by
- 36
- References
- 61
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 2 · 2018: 1
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Leukemia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- The Scholarship East Carolina University's Institutional Repository (East Carolina University) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Italian MIUR PRIN
- Bloodwise (13042)
- Intesa San Paolo Foundation
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- myelodysplastic syndrome, azacitidine, lenalidomide, acquired mutations, PIK3CD, AKT3, PLCγ2, ASXL1, TET2, RUNX1, SRSF2, loss of response, overall survival, leukemia-free survival, treatment response
- MeSH terms
- Lenalidomide, Aged, Aged, 80 and over, Azacitidine, Cell Differentiation, Female, Humans, Inositol, Male, Middle Aged, Mutation, Myelodysplastic Syndromes, Disease-Free Survival, Cell Proliferation, Kaplan-Meier Estimate
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