Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia.
Recently it was shown that, analogous to normal hematopoietic cells, the level of CXC chemokine receptor 4 (CXCR-4) expression on acute myeloid leukemia (AML) cells correlates with stromal cell derived factor-1 alpha (SDF-1)-induced chemotaxis. As we speculated that an anomalous organ distribution of AML cells could affect cell survival and thus result in an altered fraction surviving chemotherapy, we examined a possible correlation between patient prognosis and CXCR-4 expression in AML patients. We found that patients with a high CXCR-4 expression in the CD34(+) subset had a significantly reduced survival and a higher probability of relapse, resulting in a median relapse-free survival (RFS) of only 8.3 months. CXCR-4 expression was significantly higher in fetal liver tyrosine kinase-3 (Flt3)/internal tandem duplication (ITD) AML than in Flt3/wild-type (wt) AML. Covariate analysis indicated that the prognostic significance of Flt3/ITDs with respect to RFS was no more apparent when analyzed in conjunction with the expression of CXCR-4 in the CD34(+) subset, suggesting that the poor prognosis of Flt3/ITD AML might be subordinate to the increased CXCR-4 expression. Using a granulocyte colony-stimulating factor receptor (G-CSF-R)-expressing 32D cell line, we observed that SDF-1/CXCR-4 interaction is required for the survival of myeloid differentiating cells, and it also induces a block in G-CSF-induced myeloid differentiation. These data suggest that the SDF-1/CXCR-4 axis may influence therapy responsiveness and defines unfavorable prognosis in AML.
Rombouts
Elwin J C
EJ
Department of Hematology, Room Ee1391, PO Box 1738, 3000 DR Rotterdam, The Netherlands. w.rombouts@erasmusmc.nl
Pavic
Biljana
B
Löwenberg
Bob
B
Ploemacher
Rob E
RE
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000401:mortality* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D012008:Recurrence; D051941:fms-Like Tyrosine Kinase 3
D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3