title: 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: 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.
authors.affiliation: Oncology and Pediatrics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Edward Allan R
authors.initials: EA
authors.lastname: Sison
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rau
authors.forename: Emily
authors.initials: E
authors.lastname: McIntyre
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology*; D016019:Survival Analysis; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C527276:CXCR4 protein, human; C497422:KMT2A protein, human; D019718:Receptors, CXCR4; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase