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 - Funding Information:
The authors thank the patients and their families who contributed to this study. They thank the University Health Network/SickKids Flow Cytometry Facility and Robert Lopez and Mario D’Souza from the University Health Network Animal Resource Centre. The authors thank Jenny Ho for experimental assistance and Ethan Kulman for assistance with figure formatting. R.J. Vanner is the recipient of the Joseph M. West Family Memorial Fund Research Award, E. Waanders was awarded Dutch Cancer Society KUN2012-5366, and B. Porse was supported through a center grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant number NNF17CC0027852). C.G. Mullighan was supported by grants from the National Cancer Institute (NCI): R35 CA297695 and P50 CA021765. J.E. Dick was supported by funds from the Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research through funding provided by the Government of Ontario, Canadian Institutes for Health Research (Foundation: 154293, operating grant number 130412, operating grant number 89932), Canadian Cancer Society (grant number 703212), Terry Fox Research Institute Program Project Grant, and a Canada Research Chair.
Funding Information:
E. Waanders reports grants from Dutch Cancer Society during the conduct of the study. C.G. Mullighan reports personal fees from Illumina during the conduct of the study, as well as grants from Pfizer and AbbVie, and other support from Amgen outside the submitted work. J.E. Dick reports grants from Joseph M. West Family Memorial Fund Research Award, Dutch Cancer Society (KUN2012-5366), Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant number NNF17CC0027852), Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research through funding provided by the Government of Ontario, Canadian Institutes for Health Research (Foundation: 154293, operating grant number 130412, operating grant number 89932), Canadian Cancer Society (grant number 703212), Terry Fox Research Institute (Program Project Grant), and Canada Research Chair during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
©2021 American Association for Cancer Research.
PY - 2022/1
Y1 - 2022/1
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.
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.
KW - Central Nervous System Diseases/pathology
KW - Central Nervous System Neoplasms/drug therapy
KW - Central Nervous System/metabolism
KW - Humans
KW - Meningeal Neoplasms/pathology
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Protein Biosynthesis/genetics
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85128320978&partnerID=8YFLogxK
U2 - 10.1158/2643-3230.BCD-20-0216
DO - 10.1158/2643-3230.BCD-20-0216
M3 - Article
C2 - 35019858
SN - 2643-3230
VL - 3
SP - 16
EP - 31
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 1
ER -