TY - JOUR

T1 - Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target

AU - Vanner, Robert J.

AU - Dobson, Stephanie M.

AU - Gan, Olga I.

AU - McLeod, Jessica

AU - Schoof, Erwin M.

AU - Grandal, Ildiko

AU - Wintersinger, Jeff A.

AU - Garcia-Prat, Laura

AU - Hosseini, Mohsen

AU - Xie, Stephanie Z.

AU - Jin, Liqing

AU - Mbong, Nathan

AU - Voisin, Veronique

AU - Chan-Seng-Yue, Michelle

AU - Kennedy, James A.

AU - Waanders, Esmé

AU - Morris, Quaid

AU - Porse, Bo

AU - Chan, Steven M.

AU - Guidos, Cynthia J.

AU - Danska, Jayne S.

AU - Minden, Mark D.

AU - Mullighan, Charles G.

AU - Dick, John E.

N1 - Publisher Copyright: ©2021 American Association for Cancer Research.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1158/2643-3230.BCD-20-0216

DO - 10.1158/2643-3230.BCD-20-0216

M3 - Journal article

C2 - 35019858

AN - SCOPUS:85128320978

VL - 3

SP - 16

EP - 31

JO - Blood cancer discovery

JF - Blood cancer discovery

SN - 2643-3249

IS - 1

ER -