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

Arvind Singh Mer,Véronique Voisin ,Mark D Minden,Laura García‐Prat ,Aaron D Schimmer,John E Dick,Rose Hurren,Mathieu Lupien,Nergiz Dogan-Artun,Seyed Ali Madani Tonekaboni,Emily Heath ,Corey Nislow,Sisira Kadambat Nair,Mattias Rantalainen,Alex Murison,Cynthia J Guidos,Mark Gower,Gary D Bader,Liran I Shlush ,Sören Lehmann ,Benjamin Haibe‐Kains

doi:10.1038/s41467-021-21233-0

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.

Highlights

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy
We identify two subtypes, referred to as primitive and committed based on the differences in gene expression, and find that each is consistently associated with particular molecular characteristics, disease differentiation state and patient survival across multiple independent AML cohorts
We investigated whether analysis of gene expression patterns might identify molecular subtypes of NPM1-mutated AML

Summary

Introduction

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. 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. We identify two subtypes, referred to as primitive and committed based on the differences in gene expression, and find that each is consistently associated with particular molecular characteristics, disease differentiation state and patient survival across multiple independent AML cohorts. Based on the differences in gene expression, epigenomic (ATAC-seq), and immunophenotyping (CyToF), we associate subtypes with particular molecular characteristics, disease differentiation state and patient survival across multiple independent AML cohorts. This suggests that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, may be of therapeutic benefit

Methods

Results

Conclusion