MLL‐rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism

Abstract

Summary Infants with MLL-rearranged (MLL-R) acute lymphoblastic leukaemia (ALL) have a dismal prognosis. While most patients achieve remission, approximately half of patients recur with a short latency to relapse. This suggests that chemotherapy-resistant leukaemia stem cells (LSCs) survive and can recapitulate the leukaemia. We hypothesized that interactions between LSCs and the bone marrow microenvironment mediate survival and chemotherapy resistance in MLL-R ALL. Using primary samples of infant MLL-R ALL, we studied the influence of bone marrow stroma on apoptosis, proliferation, and cytotoxicity induced by the FLT3 inhibitor lestaurtinib. MLL-R ALL were differentially protected by stroma from spontaneous apoptosis compared to non-MLL-R ALL. Co-culture of bulk MLL-R ALL in direct contact with stroma or with stroma-produced soluble factors promoted proliferation and cell cycle entry. Stroma also protected bulk MLL-R ALL cells and MLL-R ALL LSCs from lestaurtinib-mediated cytotoxicity. Previous studies have demonstrated that CXCR4 mediates bone marrow microenvironment signalling. Using a xenograft model of MLL-R ALL, we demonstrated that CXCR4 inhibition with AMD3100 (plerixafor) led to markedly enhanced efficacy of lestaurtinib. Therefore, the bone marrow microenvironment is a mediator of chemotherapy resistance in MLL-R ALL and targeting leukaemia-stroma interactions with CXCR4 inhibitors may prove useful in this high-risk subtype of paediatric ALL.

Treatment of infant leukemias: challenge and promise

“…Interactions between infant MLL-r ALL leukemia stem cells and the BM stromal microenvironment via the CXCR4/SDF-1 axis have been shown to mediate survival and therapeutic resistance in MLL-r ALL. 52 Moreover, in xenograft models of MLL-r infant ALL, CXCR4 inhibition with plerixafor led to markedly enhanced in vivo efficacy of FLT3 inhibitors, suggesting that targeting leukemiastroma interactions with CXCR4 inhibitors may represent a promising adjunctive therapy. Dynamic upregulation of CXCR4 expression on the surface of acute leukemias (including MLL-r) in response to cytotoxic chemotherapy may enhance this stroma-mediated resistance and serve as a biomarker that can identify subsets of infants with leukemia for whom CXCR4 inhibition may be particularly effective.…”

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

“…Chemokine stromal-derived factor-1α (SDF-1α), which is also known as C-X-C chemokine ligand 12, and its cognate receptor, C-X-C chemokine receptor type 4 (CXCR4), which is also known as cluster of differentiation (CD)184, are considered to be critical mediators of BM microenvironment/leukemic cell interactions (14)(15)(16). Binding of SDF-1α induces conformational changes in CXCR4, resulting in its incorporation into lipid rafts and subsequent phosphorylation (17).…”

Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

“…CXCR4 antagonists can abrogate the protective effect of stromal cells on chemotherapy-induced apoptosis in AML cells [140,141]. miRNA let-7a was shown to be down-regulated by SDF-1α-mediated CXCR4 activation and increased by a CXCR4 antagonist in OCI-AML3 cells.…”