The capacity of AML cells to respond to CXCL12 by migration and calcium fluxes correlates with CXCR4 cell surface expression levels 5. Following these publications, in 2002, van Der Schoot, et al., analyzed the CXCL12 dependent migration capacity of cells derived from the BM or peripheral blood (PB) from 26 AML patients 6. progenitor cells into the circulation and enhance anti leukemic effects of chemotherapy. The hypothesis that CXCL12/CXCR4 interactions contribute to the resistance of AML cells to signal transduction inhibitor- and chemotherapy-induced apoptosis is currently being tested in a series of Phase I/II studies in humans. strong class=”kwd-title” Keywords: CXCR4, CXCL12, AML, Bone marrow, Microenvironment. Introduction Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by the uncontrolled proliferation of hematopoietic stem cells and progenitors (blasts) with a reduced capacity to differentiate into mature cells 1. Despite sensitivity to chemotherapy, long-term disease-free survival for AML patients remains low and the majority eventually relapse from minimal residual disease (MRD) 2. Bone marrow (BM) is the major site for MRD where adhesion of AML cells to bone marrow components may provide protection from the drugs 1. The chemokine receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1/CXCL12) are important players involved in the cross-talk between leukemia cells and the BM microenvironment 3. Expression of CXCR4 in AML and its prognostic significance In 1998, Kanz et al., MV1 first published that leukemic blasts (mostly CD34+) from patients with AML expressed variable amounts of CXCR4, which was functionally active, as demonstrated by a positive correlation between the CXCL12-induced migration and the cell surface density of CXCR4 (r = 0.97) 4. Later, in 2000, the same group published that AML FAB M1/2 blasts did not show calcium fluxes and migration was not stimulated by CXCL12. In myelomonocytic AML (M4/5), however, CXCL12 induced significant calcium MV1 fluxes and migration was increased by two-fold. M3 and M4 blasts with eosinophilia (M4eo) showed intermediate activity and M6 blasts showed no functional activity. The capacity of AML cells to respond to CXCL12 by migration and calcium fluxes correlates with CXCR4 cell surface expression levels 5. Following these publications, in 2002, van Der Schoot, et al., analyzed the CXCL12 dependent migration capacity of cells derived from the BM or peripheral blood (PB) from 26 AML patients 6. No differences in CXCL12-induced migration or CXCR4 expression were observed between the different AML subtypes. However, more immature leukemic cells expressing CD34, CD38 and HLA-DR were preferentially migrating, whereas cells Rabbit Polyclonal to RRM2B expressing CD14 and CD36 showed diminished migration. Analysis of paired PB and BM samples indicated that a significantly higher CXCL12-induced migration was observed in AML for CD34(+) BM-derived cells compared to CD34(+) PB-derived cells, suggesting a role for CXCL12 in the anchoring of leukemic cells in the BM. The lower percentage of circulating leukemic blasts in patients with a relatively high level of CXCL12-induced migration also supports this hypothesis 6. The prognostic significance of CXCR4 expression in patients with AML was examined by different groups. In 2004, Ploemacher, et al., analyzed the expression of CXCR4 together with the expression of CD34 in a series of 90 samples from adult patients with AML 7. They found that patients with a high CXCR4 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. CXCR4 expression was significantly higher MV1 in Fms-like tyrosine kinase-3 (Flt3)/internal tandem duplication (ITD) AML than in Flt3/wild-type (wt) AML. A 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 CXCR4 in the CD34+ subset, suggesting that the poor prognosis of Flt3/ITD AML might be subordinate to the increased CXCR4 expression. These data suggest that the CXCL12/CXCR4 axis may influence therapy responsiveness and define unfavorable prognosis in AML 7. Furthermore, in AML with flt3-ITD mutation, the elevated level.
