Leukemic Stem Cells Activate Lineage Inappropriate Signalling Pathways to Promote Their Growth

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Feb 14

PMID 38355578

Authors

Sophie G Kellaway

Sandeep Potluri

Peter Keane

Helen J Blair

Luke Ames

Alice Worker

Paulynn S Chin

Anetta Ptasinska

Polina K Derevyanko

Assunta Adamo

Daniel J L Coleman

Naeem Khan

Salam A Assi

Anja Krippner-Heidenreich

Manoj Raghavan

Peter N Cockerill

Olaf Heidenreich

Constanze Bonifer

Affiliations

Soon will be listed here.

Abstract

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

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