1. Biological and therapeutic implications of a unique subtype of NPM1 mutated AML
- Author
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Corey Nislow, Sören Lehmann, Alex Murison, Gary D. Bader, Mark Gower, Liran I. Shlush, Benjamin Haibe-Kains, Nergiz Dogan-Artun, Rose Hurren, John E. Dick, Veronique Voisin, Cynthia J. Guidos, Sisira Kadambat Nair, Seyed Ali Madani Tonekaboni, Mathieu Lupien, Emily Heath, Mark D. Minden, Aaron D. Schimmer, Laura García-Prat, Arvind Singh Mer, and Mattias Rantalainen
- Subjects
0301 basic medicine ,Drug ,NPM1 ,Medicin och hälsovetenskap ,media_common.quotation_subject ,Science ,General Physics and Astronomy ,Disease ,Biology ,Medical and Health Sciences ,Article ,Acute myeloid leukaemia ,General Biochemistry, Genetics and Molecular Biology ,Immunophenotyping ,Prognostic markers ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Machine learning ,Cluster Analysis ,Humans ,Protein Kinase Inhibitors ,Epigenomics ,media_common ,Multidisciplinary ,Gene Expression Regulation, Leukemic ,Kinase ,Nuclear Proteins ,Reproducibility of Results ,Myeloid leukemia ,General Chemistry ,Survival Analysis ,Chromatin ,Leukemia, Myeloid, Acute ,Phenotype ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Stem cell ,Nucleophosmin ,Biomarkers - 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., Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.
- Published
- 2021