Cited by 37Acute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processesChromatin Remodeling and Cancer

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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Follo, Matilde Y., Pellagatti, Andrea, Armstrong, Richard N., Ratti, Stefano, Mongiorgi, Sara, De Fanti, Sara, Bochicchio, Maria Teresa, Russo, Domenico +12 more·2019·Leukemia

Abstract

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).”
  • 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).”

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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
Venue
Leukemia
Published
2019-02-20
Volume
33
Issue
9
Pages
2276-2290
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
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
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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