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Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.

SUBMITTER: Naldini MM

PROVIDER: S-EPMC9995364 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

Naldini Matteo Maria MM Casirati Gabriele G Barcella Matteo M Rancoita Paola Maria Vittoria PMV Cosentino Andrea A Caserta Carolina C Pavesi Francesca F Zonari Erika E Desantis Giacomo G Gilioli Diego D Carrabba Matteo Giovanni MG Vago Luca L Bernardi Massimo M Di Micco Raffaella R Di Serio Clelia C Merelli Ivan I Volpin Monica M Montini Eugenio E Ciceri Fabio F Gentner Bernhard B

Nature communications 20230308 1

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy ...[more]

PMID: 36890137

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Project description:Background: A fundamental hallmark of cancer cells is their ability to sustain proliferative signaling and cell survival, reflected in a cellular chemotherapy response that is poorly understood. We questioned whether chemotherapy modulated phospho-signaling at 4 and 24 h in vivo could provide information about long-term survival in acute myeloid leukemia (AML), and if the signaling response to therapy was more informative than analysis at time of diagnosis. Methods: Peripheral blood was collected from 32 younger AML patients (age 16-74 years), before, 4- and 24 hours after start of induction chemotherapy. Samples were analyzed by 36-dimensional mass cytometry for assessment of alterations in immunophenotypes and intracellular signaling using unsupervised and supervised machine learning approaches. Results were validated by RNA sequencing and mass spectrometry proteomics (Super SILAC). Targeted sequencing was used to characterize patient samples for recurrent AML mutations. Drug sensitivity and resistance testing ex vivo was compared to activation of relevant signal transduction pathways and mutational profile. Findings: 5-year patient survival was accurately predicted in the leukemic cell population at 24 hours after therapy onset by phospho-proteins p-ERK1/2 (T202/Y204) and p-p38 (T180/Y182). RNA sequencing showed induction of MAPK target gene expression and the AP-1 transcription complex in patients with high p-ERK1/2. Super-SILAC proteomics confirmed an increase in the abundance of p38 prime target MAPKAPK2(MK2) 24 hours after start of induction therapy. Ex vivo drug sensitivity testing demonstrated high sensitivity to MEK inhibitors in the patient cells with high p-ERK1/2 measured at diagnosis or 24 hours after start of chemotherapy. Interpretation: Early single cell signaling response to chemotherapy provided precise prognostic information independent of stratification by genetics. We propose that early functional measurement of chemotherapy-potentiated MAPK pathway signaling could identify non-responders to intensive chemotherapy allowing precise treatment adjustment.

Dataset Information

Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

Publications

Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

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