SF3B1 Mutant MDS-initiating Cells May Arise from the Haematopoietic Stem Cell Compartment

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Dec 9

PMID 26643973

Citations 51

Authors

Syed A Mian

Kevin Rouault-Pierre

Alexander E Smith

Thomas Seidl

Irene Pizzitola

Aytug Kizilors

Austin G Kulasekararaj

Dominique Bonnet

Ghulam J Mufti

Affiliations

Soon will be listed here.

Abstract

Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.

Citing Articles

SF3B1: from core splicing factor to oncogenic driver.

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Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition.

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Influence of donor-recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation.

Mian S, Ariza-McNaughton L, Anjos-Afonso F, Guring R, Jackson S, Kizilors A Hemasphere. 2024; 8(5):e80.

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