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Multi-omic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target

ABSTRACT: Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing, transcriptional and proteomic profiling of paired leukemia infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3) and drug targeting of C3 influenced CNS disease in xenografts. CNS infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies therapeutic targeting of mRNA translation as a novel therapeutic approach for B-ALL leptomeningeal disease.

PROVIDER: EGAS00001005647 | EGA |

REPOSITORIES: EGA

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Central nervous system involvement of acute lymphoblastic leukemia depends on mRNA translation and complement component 3

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.

2023-03-11 | PXD022411 | Pride

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Expression data from xenografted human leukemia cells comparing leukemic cells engrafted in the central nervous system (CNS) to leukemic cells derived from bone marrow (BM)

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2017-07-19 | GSE89710 | GEO

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