Relationship between CXC chemokine receptor 4 expression and prognostic significance in acute myeloid leukemia

Abstract

CXC chemokine receptor 4 (CXCR4) expression on acute myeloid leukemia (AML) cells correlated with stromal cell derived factor-1α (SDF-1α) and retained hematopoietic progenitors and leukemia cells within the bone marrow microenvironment. Here, we examined CXCR4 expression in 134 de novo AML and 21 controls by flow cytometry, evaluated the relationship between CXCR4 expression and clinical characteristics, and elucidated the prognostic significance of CXCR4 expression in AML prospectively. We found that the CXCR4 expression was significantly higher in AML patients than controls ( P = .000). One hundred thirty four cases of de novo AML patients were divided into 2 groups according to the median of CXCR4 relative fluorescence intensity (RFI). CXCR4 high group (RFI >4.23) had markedly shorter overall survival (OS) and disease-free survival (DFS) than CXCR4 low group (RFI ≤4.23) in 106 AML patients who received chemotherapy ( P = .002; .026, respectively). Furthermore, in the 87 non-M3 patients who received induction therapy, there was a significant decrease for OS but not for DFS in the CXCR4 high group ( P = .047 and .178, respectively). Moreover, high levels of CXCR4 expression independently increased the risk of relapse in both all AML and non-M3 patients who achieved complete remission (CR) after chemotherapy (odds ratio = 1.090, P = .010; odds ratio = 1.068, P = .048, respectively). Collectively, our data suggest that CXCR4 overexpression was an independent prognostic factor for disease relapse and poorer OS in both all AML and non-M3 patients. CXCR4 expression levels can be determined at disease presentation by the flow rapidly and easily. As such, CXCR4 could be used as a potential therapeutic target in AML patients with poor prognosis.

Targeting CXCR4 in AML and ALL

“…This is potentially due to the role CXCR4 plays in keeping leukemic cells within the bone marrow as well as its roles in activating pathways that favor the survival, growth, and chemotherapy resistance of these malignant cells (1). Leukemic blasts with high CXCR4 expression in cases of AML was associated with higher rates of relapse and lower overall survival (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Patients with a FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) or nucleophosmin mutation express significantly more CXCR4 than their wildtype counterparts (27-29, 31, 32, 36).…”

“…However, these cytogenetic abnormalities do not solely account for the elevated CXCR4 expression in the disease as high CXCR4 expression is still a risk factor for prognosis in normal karyotype patients with AML (29,30). Further, CXCR4 in French American British (FAB) AML-M4 and M5 subtypes is significantly increased relative to the other FAB and World Health Organization (WHO) AML subtypes (27)(28)(29)31).…”

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

“…LSCs can compete with HSCs and exploit the CXCL12-CXCR4 axis to their advantage. Indeed, most AML blasts and especially LSCs acquire CXCR4 expression [44,45]. Moreover, high CXCR4 expression on AML is a negative prognostic factor associated with reduced overall and relapse-free survival [46].…”

T22-PE24-H6 Nanotoxin Selectively Kills CXCR4-High Expressing AML Patient Cells In Vitro and Potently Blocks Dissemination In Vivo

“…The interaction of the CXCR4 receptor with its ligand, CXCL12, regulates the signaling between AML cells and the bone marrow (BM) microenvironment that promotes migration and resistance to chemotherapy [ 7 , 11 ]. In addition, CXCR4 is highly expressed in around 50% of AML patients [ 12 , 13 , 14 , 15 , 16 ] and its overexpression correlates with a poor prognosis, which suggests that CXCR4 is an AML potential therapeutic target [ 12 , 17 , 18 , 19 ].…”