Impact of Concomitant Aberrant CD200 and BCL2 Overexpression on Outcome of Acute Myeloid Leukemia: A Cohort Study from a Single Center

Objective: CD200 and BCL2 overexpression is independently associated with inferior survival in acute myeloid leukemia (AML), and these two factors are frequently co-expressed; however, no data are available on the role of concomitant aberrant CD200 and BCL2 expression on outcome of AML patients. We aimed to elucidate the prognostic role of CD200/BCL2 co-expression and its association with specific leukemia subsets. Materials and Methods: We analyzed 242 adult AML patients uniformly treated with intensive chemotherapy, evaluating the impact of CD200 and BCL2 expression on complete remission (CR), disease-free survival, and overall survival (OS). Results: CD200 and BCL2 were expressed in 139 (57.4%) and 137 (56.6%) cases, respectively, with 92 patients (38%) displaying double positivity (DP), 58 (24%) displaying double negativity (DN), and 92 patients expressing only either CD200 (n=47) or BCL2 (n=45). CR was achieved in 71% of cases, being less frequent in DP patients (60%) compared to other groups (76%-81%, p<0.001). In the whole population 3-year OS was 44%, being lower in DP patients (28%) than in patients with single CD200 or BCL2 expression (47%) or DN cases (60%; p=0.004). Other factors associated with worse OS were advanced age, CD34 positivity, secondary AML, and high white blood cell count at diagnosis; combining these 4 factors with CD200/BCL2 DP, we identified 6 groups with significantly different rates of survival (3-year OS ranging from 90% to 0%). Conclusion: Our data support a synergistic effect of CD200 and BCL2 in AML cells, conferring an enhanced survival capacity in a permissive microenvironment and resulting in worse prognosis.

[1]  J. Karp,et al.  Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells , 2015, Genes & development.

[2]  W. Pierceall,et al.  Mitochondrial Profiling of Acute Myeloid Leukemia in the Assessment of Response to Apoptosis Modulating Drugs , 2015, PloS one.

[3]  R. Fanin,et al.  Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors , 2015, Oncotarget.

[4]  J. Engelman,et al.  The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics. , 2015, Cancer discovery.

[5]  C. Drake,et al.  Immune checkpoint blockade: a common denominator approach to cancer therapy. , 2015, Cancer cell.

[6]  H. Ahsan,et al.  The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update , 2015, Archives of Toxicology.

[7]  R. LaRue,et al.  CD200 in CNS tumor-induced immunosuppression: the role for CD200 pathway blockade in targeted immunotherapy , 2014, Journal of Immunotherapy for Cancer.

[8]  J. Aerts,et al.  Immunomodulation in cancer. , 2014, Current opinion in pharmacology.

[9]  P. Johnston,et al.  Cancer drug resistance: an evolving paradigm , 2013, Nature Reviews Cancer.

[10]  J. Aurelius,et al.  Immunotherapeutic strategies for relapse control in acute myeloid leukemia. , 2013, Blood reviews.

[11]  G. Gillet,et al.  Non-apoptotic roles of Bcl-2 family: the calcium connection. , 2013, Biochimica et biophysica acta.

[12]  K. Alimoghaddam,et al.  Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia , 2013, Tumor Biology.

[13]  C. Schiffer,et al.  Genetic biomarkers in acute myeloid leukemia: will the promise of improving treatment outcomes be realized? , 2012, Expert review of hematology.

[14]  L. Meyaard,et al.  CD200R signaling in tumor tolerance and inflammation: A tricky balance. , 2012, Current opinion in immunology.

[15]  Heping Cheng,et al.  Calcium gradients underlying cell migration. , 2012, Current opinion in cell biology.

[16]  Z. Berneman,et al.  Natural killer cell immune escape in acute myeloid leukemia , 2012, Leukemia.

[17]  R. Hills,et al.  Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells , 2012, Leukemia.

[18]  R. Hills,et al.  Expression of CD200 on AML blasts directly suppresses memory T-cell function , 2012, Leukemia.

[19]  R. Hills,et al.  CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia , 2011, Leukemia.

[20]  R. Hills,et al.  Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. , 2010, Blood.

[21]  Y. Eliezri,et al.  The immunosuppressive surface ligand CD200 augments the metastatic capacity of squamous cell carcinoma. , 2010, Cancer research.

[22]  W. Farrar,et al.  Cancer stem cells, CD200 and immunoevasion. , 2008, Trends in immunology.

[23]  A. Barclay,et al.  A critical function for CD200 in lung immune homeostasis and the severity of influenza infection , 2008, Nature Immunology.

[24]  T. Rème,et al.  CD200: a putative therapeutic target in cancer. , 2008, Biochemical and biophysical research communications.

[25]  R. Hills,et al.  CD200 as a prognostic factor in acute myeloid leukaemia , 2007, Leukemia.

[26]  A. Venditti,et al.  Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). , 2003, Blood.

[27]  H. Ackermann,et al.  The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia , 2002, Leukemia.

[28]  R. Gorczynski,et al.  Evidence of a role for CD200 in regulation of immune rejection of leukaemic tumour cells in C57BL/6 mice , 2001, Clinical and experimental immunology.

[29]  J. Dichgans,et al.  BCL‐2 promotes migration and invasiveness of human glioma cells , 1998, FEBS letters.

[30]  C. Leonetti,et al.  Bcl‐2 overexpression enhances the metastatic potential of a human breast cancer line , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  H. Pahl,et al.  Activation of NF‐κB by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers , 1996, FEBS letters.

[32]  J. Magaud,et al.  High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. , 1993, Blood.

[33]  C. Higgins,et al.  ABC transporters: from microorganisms to man. , 1992, Annual review of cell biology.

[34]  Y. Assaraf,et al.  Lysosomes as mediators of drug resistance in cancer. , 2016, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[35]  S. Shukla,et al.  Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. , 2013, Neoplasma.

[36]  B. Bauvois New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. , 2012, Biochimica et biophysica acta.

[37]  Roberta Riccioni,et al.  Deregulation of apoptosis in acute myeloid leukemia. , 2007, Haematologica.

[38]  R. Fanin,et al.  The prognostic value of P-glycoprotein (ABCB) and breast cancer resistance protein (ABCG2) in adults with de novo acute myeloid leukemia with normal karyotype. , 2006, Haematologica.

[39]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.

[40]  F. Giles New drugs in acute myeloid leukemia , 2002, Current oncology reports.