Project description:In order to elucidate mechanism of resistance to BTKi and dasatinib in CNS-infiltrating leukemia cells and to investigate the CNS homing of E2A-PBX1/preBCR+ ALL cells, we performed global transcriptome analysis by RNA sequencing. RNA was isolated from CNS-infiltrating cells from vehicle, dasatinib, ibrutinib, dasatinib + ibrutinib-treated mice
Project description:CNS leukemia is still the major obstacle in treating childhood acute lymphoblastic leukemia (ALL). We have used our NOD/SCID/huALL xenotransplantation model to identify molecular pathways leading to the infiltration of leukemic cells into the CNS compartment. We analysed gene expression differences of leukemic cells isolated from CNS and BM of CNS-positive samples using a microarray approach to detect expression differences between different infiltrated compartments.
Project description:We present a detailed genetic, transcriptional and physiological study of leukemic cells isolated from the CNS and bone marrows (BM) of both affected children and xenograft model of B-ALL which recapitulate the key features of CNS involvement. We reveal that leukemic cells in CNS possess distinct hypoxic signature such as proliferation suppression, decrease of mitochondrial oxidative phosphorylation and increase of glycolysis compared with leukemic cells in BM.
Project description:We present a detailed genetic, transcriptional and physiological study of leukemic cells isolated from the CNS and bone marrows (BM) of both affected children and xenograft model of B-ALL which recapitulate the key features of CNS involvement. We reveal that leukemic cells in CNS possess distinct hypoxic signature such as proliferation suppression, decrease of mitochondrial oxidative phosphorylation and increase of glycolysis compared with leukemic cells in BM.
Project description:Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has a poor prognosis and remains a therapeutic challenge with few recent advances in therapy. Leptomeningeal disease is particularly common in the high risk subgroup of KMT2A-rearranged B-ALL (KMT2A-r B-ALL). Here we performed transcriptional and proteomic profiling of leukemia cells from bone marrow (BM) and CNS-disseminated disease in KMT2A-r B-ALL xenografts. CNS disease exhibited stemness traits and metabolic reprogramming previously associated with chemotherapy resistance. Genes governing mRNA translation were upregulated in CNS samples, a finding confirmed in cohorts of KMT2A-r B-ALL patients with CNS involvement. This upregulation was functionally important for CNS disease as the mRNA translational inhibitor omacetaxine mepesuccinate (OMA) significantly reduced leptomeningeal disease burden in xenografts. Proteomic analysis demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3), a known driver of leptomeningeal metastasis in solid tumours, pointing to a convergent mechanism for this route of metastasis in multiple cancers. Pharmacological inhibition of C3a signaling suppressed CNS dissemination, whereas C3a receptor activation increased CNS disease. Overall, our study identifies mRNA translation and a set of secreted proteins as key mediators of CNS dissemination in KMT2A-r B-ALL. Therapeutic targeting of these dependencies represents a novel approach to prevent or treat leptomeningeal disease.