TY - JOUR
T1 - CXC chemokine receptor 4 expression, CXC chemokine receptor 4 activation, and wild-type nucleophosmin are independently associated with unfavorable prognosis in patients with acute myeloid leukemia
AU - Konoplev, Sergej
AU - Lin, Pei
AU - Yin, C. Cameron
AU - Lin, E.
AU - Nogueras González, Graciela M.
AU - Kantarjian, Hagop M.
AU - Andreeff, Michael
AU - Medeiros, L. Jeffrey
AU - Konopleva, Marina
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grants CA016672 , P30 CA016672 , and 2P50 CA100632-06 . The authors have stated that they have no conflicts of interest.
PY - 2013/12
Y1 - 2013/12
N2 - Background CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in patients with AML and predicts a favorable prognosis. In vitro studies have suggested that mutant nucleophosmin (NPM) decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways. Patients and Methods In a group of 117 untreated adults with AML, we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated CXCR4 (pCXCR4) expression. All cases also were analyzed for NPM1 mutations using polymerase chain reaction-based methods. Results CXCR4 expression was detected in 75 patients (64%), and pCXCR4 expression was detected in 31 patients (26%). NPM1 mutations were detected in 63 patients (54%). NPM1 mutations did not correlate with CXCR4 (P =.212) or pCXCR4 (P =.355) expression. The median 5-year overall survival was 27% (95% confidence interval, 19-36), with a median follow-up of 8 months (95% confidence interval, 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematologic disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild-type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival. Conclusions There is no correlation between NPM1 mutations and CXCR4 or pCXCR4 expression, suggesting that the CXCR4 and NPM pathways act independently in adult AML.
AB - Background CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in patients with AML and predicts a favorable prognosis. In vitro studies have suggested that mutant nucleophosmin (NPM) decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways. Patients and Methods In a group of 117 untreated adults with AML, we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated CXCR4 (pCXCR4) expression. All cases also were analyzed for NPM1 mutations using polymerase chain reaction-based methods. Results CXCR4 expression was detected in 75 patients (64%), and pCXCR4 expression was detected in 31 patients (26%). NPM1 mutations were detected in 63 patients (54%). NPM1 mutations did not correlate with CXCR4 (P =.212) or pCXCR4 (P =.355) expression. The median 5-year overall survival was 27% (95% confidence interval, 19-36), with a median follow-up of 8 months (95% confidence interval, 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematologic disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild-type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival. Conclusions There is no correlation between NPM1 mutations and CXCR4 or pCXCR4 expression, suggesting that the CXCR4 and NPM pathways act independently in adult AML.
KW - AML
KW - Acute myeloid leukemia
KW - CXCR4
KW - CXCR4 activation
KW - CXCR4 phosphorylation
KW - NPM1
KW - Prognosis
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U2 - 10.1016/j.clml.2013.05.013
DO - 10.1016/j.clml.2013.05.013
M3 - Article
C2 - 24035716
AN - SCOPUS:84888010357
SN - 2152-2650
VL - 13
SP - 686
EP - 692
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 6
ER -