BCL2L10 is a predictive factor for resistance to Azacitidine in MDS and AML patients

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 family 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.

[1]  H. Varmus,et al.  Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1 , 2012, Proceedings of the National Academy of Sciences.

[2]  Li Ding,et al.  RECURRENT MUTATIONS IN THE U2AF1 SPLICING FACTOR IN MYELODYSPLASTIC SYNDROMES , 2011, Nature Genetics.

[3]  M. Stratton,et al.  Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. , 2011, The New England journal of medicine.

[4]  S. Sugano,et al.  Frequent pathway mutations of splicing machinery in myelodysplasia , 2011, Nature.

[5]  B. Esterni,et al.  Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  G. Robert,et al.  Azacitidine-resistant SKM1 myeloid cells are defective for AZA-induced mitochondrial apoptosis and autophagy , 2011, Cell cycle.

[7]  M. Vignetti,et al.  Role of BCL2L10 methylation and TET2 mutations in higher risk myelodysplastic syndromes treated with 5-Azacytidine , 2011, Leukemia.

[8]  D. Neuberg,et al.  Clinical effect of point mutations in myelodysplastic syndromes. , 2011, The New England journal of medicine.

[9]  B. Quesnel,et al.  Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias , 2011, Leukemia.

[10]  J. Licht,et al.  DNMT3A mutations in acute myeloid leukemia , 2011, Nature Genetics.

[11]  Li Ding,et al.  Recurrent DNMT3A Mutations in Patients with Myelodysplastic Syndromes , 2011, Leukemia.

[12]  A. Stamatoullas,et al.  Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. , 2011, Blood.

[13]  R. Arceci.  Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias , 2011 .

[14]  T. Furuya,et al.  Loss of BCL2L10 protein expression as prognostic predictor for poor clinical outcome in gastric carcinoma , 2010, Histopathology.

[15]  Giuseppe Leone,et al.  Analysis of genome-wide methylation and gene expression induced by 5-aza-2′-deoxycytidine identifies BCL2L10 as a frequent methylation target in acute myeloid leukemia , 2010, Leukemia & lymphoma.

[16]  O. Yokosuka,et al.  BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer. , 2010, Oncology reports.

[17]  P. Auberger,et al.  Targeting lysosomes to eradicate imatinib-resistant chronic myelogenous leukemia cells , 2010, Leukemia.

[18]  D. Murray,et al.  5-Aza-2'-deoxycytidine sensitizes busulfan-resistant myeloid leukemia cells by regulating expression of genes involved in cell cycle checkpoint and apoptosis. , 2010, Leukemia research.

[19]  H. Dombret,et al.  Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  G. Robert,et al.  Cathepsin B release after imatinib-mediated lysosomal membrane permeabilization triggers BCR–ABL cleavage and elimination of chronic myelogenous leukemia cells , 2010, Leukemia.

[21]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[22]  Valeria Santini,et al.  Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. , 2009, The Lancet. Oncology.

[23]  Kangseok Lee,et al.  HIP1R Interacts with a Member of Bcl-2 Family, BCL2L10, and Induces BAK-dependent Cell Death , 2009, Cellular Physiology and Biochemistry.

[24]  J. Winter,et al.  Bcl-B Expression in Human Epithelial and Nonepithelial Malignancies , 2008, Clinical Cancer Research.

[25]  D. Haase.  Cytogenetic features in myelodysplastic syndromes , 2008, Annals of Hematology.

[26]  John Calvin Reed,et al.  Differential Regulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B and Mcl-1* , 2008, Journal of Biological Chemistry.

[27]  John Calvin Reed,et al.  Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. , 2007, Blood.

[28]  S. Grosso,et al.  Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition , 2007, Oncogene.

[29]  John M Bennett,et al.  Decitabine improves patient outcomes in myelodysplastic syndromes , 2006, Cancer.

[30]  J. Inazawa,et al.  Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance , 2004, Cancer Research.

[31]  C. Bloomfield,et al.  Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  A. Godzik,et al.  Characterization of the anti-apoptotic mechanism of Bcl-B. , 2003, The Biochemical journal.

[33]  P. Auberger,et al.  The protective effect of phorbol esters on Fas-mediated apoptosis in T cells. Transcriptional and postranscriptional regulation , 2002, Oncogene.

[34]  A. Godzik,et al.  Bcl-B, a Novel Bcl-2 Family Member That Differentially Binds and Regulates Bax and Bak* , 2001, The Journal of Biological Chemistry.

[35]  M. Lübbert,et al.  Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  T Hamblin,et al.  International scoring system for evaluating prognosis in myelodysplastic syndromes. , 1997, Blood.