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

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.

The potential role of nucleophosmin (NPM1) in the development of cancer

“…The study by Mer et al (2021) showed heterogeneity among NPM1 mutated AML patients based on stemness and recommend that the possibility of adding kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, might have a therapeutic benefit.…”

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

“…However, the impact of additional molecular lesions on NPM1-mutated-specific T-cell responses warrants further investigations in larger patient series. Relevant to this, Mer et al, recently identified two distinct subtypes within NPM1-mutated AML patients, referred to as "primitive" or "committed", based on the respective presence or absence of a stem cell signature [90]. Using gene expression profiling, epigenomic and immunophenotyping, each subtype was associated with particular molecular characteristics, disease differentiation state, and patients survival.…”

“…Of note, in the "committed" subtype, immunomodulatory genes, such as CD163 and CD14, were up-regulated. Additionally, immune response pathways such as IFNγ-mediated signaling, GPCR signaling, and toll-like receptor signaling were up-regulated in this disease subgroup, with potential implications also in occurrence or persistence of NPM1-mutated-specific immune responses, to be prospectively investigated [90]. Although generally associated with favorable prognosis, especially in the absence of FLT3-ITD, approximately 50% of NPM1-mutated AML patients receiving conventional treatment approaches, based on chemotherapy and HSCT procedures, still currently die due to disease relapse and progression [7,8,87].…”

Single-cell RNA sequencing reveals a novel cell type and immunotherapeutic targets in papillary thyroid cancer

“…Genomic and transcriptomic studies have revealed a huge number of driver mutations, abnormal regulatory programs, and disease subtypes in major human tumors 16, 17, 18, 19 . However, the conventional bulk sequencing frequently adopted in these studies only revealed the overall biological characteristics of each tumor and lacked the ability to capture signatures in intratumoral and intercellular heterogeneity.…”