Dynamic Chemotherapy-Induced Upregulation of CXCR4 Expression: A Mechanism of Therapeutic Resistance in Pediatric AML

Abstract

Cure rates in pediatric acute myeloid leukemia (AML) remain suboptimal. Overexpression of the surface receptor CXCR4 is associated with poor outcome in acute lymphoblastic leukemia (ALL) and AML. Certain non-chemotherapeutic agents have been shown to modulate CXCR4 expression and alter leukemia interactions with stromal cells in the bone marrow microenvironment. Because chemotherapy is the mainstay of AML treatment, we hypothesized that standard cytotoxic chemotherapeutic agents induce dynamic changes in leukemia surface CXCR4 expression, and that chemotherapy-induced upregulation of CXCR4 represents a mechanism of acquired chemotherapy resistance. Here, we show that cell lines variably upregulate CXCR4 with chemotherapy treatment. Those that showed upregulation were differentially protected from chemotherapy-induced apoptosis when co-cultured with stroma. We further explored the functional effects of chemotherapy-induced CXCR4 upregulation in an AML cell line (MOLM-14, which consistently upregulated CXCR4) and primary samples. We found enhanced stromal-cell derived factor-1α (SDF-1α)-mediated chemotaxis and stromal protection from additional chemotherapy-induced apoptosis. Further, treatment with the CXCR4 inhibitor plerixafor preferentially decreased stromal protection in cells with higher chemotherapy-induced upregulation of surface CXCR4. Upregulation of surface CXCR4 by standard chemotherapy may represent a mechanism of chemotherapy resistance in pediatric AML and may be a biomarker that can identify optimal patients for CXCR4 inhibition.

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

“…Nevertheless, our results suggest that upregulation of CXCR4 is a mechanism of therapy resistance in relapsed TCF3-PBX1 BCP-ALL. Similar observations have been made in BCP-ALL 19 as well as pediatric AML, 20 and provide a rationale for targeting CXCR4 either by direct antagonists such as plerixafor 21 or by downstream inhibitors of CXCR4 signaling such as dasatinib. 22 In CLL, idelalisib inhibits chemokine receptor signaling in leukemia cells causing mobilization of leukemia cells into the bloodstream, which manifests clinically as transient lymphocytosis.…”

Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia

“…17,[37][38][39] In a pediatric AML cohort, blast CXCR4 surface expression was increased by chemotherapy and contributed to resistance. 40 There was no significant difference in CXCR4 surface expression between prognostic groups according to the modified ELN prognostic system 34 in our cohort, possibly due to sample size. In agreement with previous studies, CXCR4 surface expression in our cohort was highly variable.…”

The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: A systematic review

“…Those that upregulated CXCR4 were protected from chemotherapy-induced apoptosis when cocultured with bone marrow stromal cells. Treatment with AMD3100 decreased stromal protection of myeloblasts 127 . There are several other mechanisms for overcoming the CXCR4/SDF-1α axis.…”