Abstract
In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.
Original language | English |
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Article number | 1054 |
Number of pages | 13 |
Journal | Nature Communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
Publication status | Published Online - 16 Feb 2021 |
Funding
This research was supported by the Princess Margaret Cancer Foundation, Canadian Institutes of Health Research (CIHR), including the Canadian Epigenetics, Environment and Health Research Consortium (CEEHRC) initiative, the Ontario Institute for Cancer Research (OICR) through funding provided by the Government of Ontario. We acknowledge the Princess Margaret Genomics and Bioinformatics group for providing the infrastructure required to conduct analyses included in this work. We thank the Leucegene and the Quebec Leukemia Cell Bank (BCLQ) teams for RNASeq and clinical data of the Leucegene AML cohort. The Leucegene project is supported by grants from the Government of Canada through Genome Canada and the Ministère de l′Économie, de l’Innovation du Québec through Génome Québec. Contributions - A.S.M. designed the study, collected the data, performed the data analysis, results interpretation, and wrote the manuscript. E.M.H. performed sequencing library preparation, ex vivo drug screening, data processing, and contributed to results interpretation and manuscript writing. S.K.N., L.S., M.R., S.L. and J.E.D. contributed to the data collection, analysis, results interpretation, and manuscript writing. S.A.M.T., N.D.-A., A.M. and M.L. conducted epigenomic profiling and data analysis. L.G., R.H. and C.N. participated in qPCR analysis and gene expression profiling. V.V. and G.D.B. performed cellular deconvolution analysis. M.G. and C.J.G. conducted mass cytometry profiling and data analysis. M.D.M., A.D.S. and B.H.K. designed and supervised the study. Funding Information: A.D.S. has received research funding from Takeda Pharmaceuticals and Medivir AB, and consulting fees/honorarium from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals. A.D.S. holds stock in Abbvie. A.D.S. is an inventor on patent applications claiming the use of DNTs for the treatment of AML. All other authors declare no competing interests. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
All Science Journal Classification (ASJC) codes
- General Chemistry
- General Biochemistry,Genetics and Molecular Biology
- General Physics and Astronomy