title: BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients.
abstract: Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients.
authors.affiliation: INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team Cell Death, Differentiation, Inflammation and Cancer, Nice, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mounier
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Karsenti
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Jill-Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Sophie
authors.initials: S
authors.lastname: Raynaud
authors.forename: Frederic
authors.initials: F
authors.lastname: Luciano
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D001374:Azacitidine / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016019:Survival Analysis; D019076:Transgenes / Q000235:genetics
chemical_list: C117144:BCL2-like 10 protein; D054316:Biomarkers, Pharmacological; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D001374:Azacitidine