Biological and therapeutic implications of a unique subtype of NPM1 mutated AML

Arvind Singh Mer, Emily M. Heath, Seyed Ali Madani Tonekaboni, Nergiz Dogan-Artun, Sisira Kadambat Nair, Alex Murison, Laura Garcia-Prat, Liran Shlush, Rose Hurren, Veronique Voisin, Gary D. Bader, Corey Nislow, Mattias Rantalainen, Soren Lehmann, Mark Gower, Cynthia J. Guidos, Mathieu Lupien, John E. Dick, Mark D. Minden, Aaron D. Schimmer () and Benjamin Haibe-Kains ()
Additional contact information
Arvind Singh Mer: University Health Network
Emily M. Heath: University Health Network
Seyed Ali Madani Tonekaboni: University Health Network
Nergiz Dogan-Artun: University Health Network
Sisira Kadambat Nair: University Health Network
Alex Murison: University Health Network
Laura Garcia-Prat: University Health Network
Liran Shlush: Weizmann Institute of Science
Rose Hurren: University Health Network
Veronique Voisin: University of Toronto
Gary D. Bader: University of Toronto
Corey Nislow: The University of British Columbia
Mattias Rantalainen: Karolinska Institute
Soren Lehmann: Karolinska Institute
Mark Gower: The Hospital for Sick Children
Cynthia J. Guidos: The Hospital for Sick Children
Mathieu Lupien: University Health Network
John E. Dick: University Health Network
Mark D. Minden: University Health Network
Aaron D. Schimmer: University Health Network
Benjamin Haibe-Kains: University Health Network

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21233-0

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DOI: 10.1038/s41467-021-21233-0

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