Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target

Robert J. Vanner, Stephanie M. Dobson, Olga I. Gan, Jessica McLeod, Erwin M. Schoof, Ildiko Grandal, Jeff A. Wintersinger, Laura Garcia-Prat, Mohsen Hosseini, Stephanie Z. Xie, Liqing Jin, Nathan Mbong, Veronique Voisin, Michelle Chan-Seng-Yue, James A. Kennedy, Esmé Waanders, Quaid Morris, Bo Porse, Steven M. Chan, Cynthia J. GuidosJayne S. Danska, Mark D. Minden, Charles G. Mullighan, John E. Dick

Research output: Contribution to journalJournal articleResearchpeer-review

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 as well as 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 targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. SIGNIFICANCE: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition.This article is highlighted in the In This Issue feature, p. 1.
Original languageEnglish
JournalBlood Cancer Discovery
Volume3
Issue number1
Pages (from-to)16-31
Number of pages16
ISSN2643-3249
DOIs
Publication statusPublished - 2022

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