A stemness screen reveals C3orf54/INKA1 as a promoter of human leukemia stem cell latency.

Blood
Kerstin B KaufmannJohn E Dick

Abstract

There is a growing body of evidence that the molecular properties of leukemia stem cells (LSCs) are associated with clinical outcomes in acute myeloid leukemia (AML), and LSCs have been linked to therapy failure and relapse. Thus, a better understanding of the molecular mechanisms that contribute to the persistence and regenerative potential of LSCs is expected to result in the development of more effective therapies. We therefore interrogated functionally validated data sets of LSC-specific genes together with their known protein interactors and selected 64 candidates for a competitive in vivo gain-of-function screen to identify genes that enhanced stemness in human cord blood hematopoietic stem and progenitor cells. A consistent effect observed for the top hits was the ability to restrain early repopulation kinetics while preserving regenerative potential. Overexpression (OE) of the most promising candidate, the orphan gene C3orf54/INKA1, in a patient-derived AML model (8227) promoted the retention of LSCs in a primitive state manifested by relative expansion of CD34+ cells, accumulation of cells in G0, and reduced output of differentiated progeny. Despite delayed early repopulation, at later times, INKA1-OE resulted in the e...Continue Reading

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Citations

Jan 30, 2021·Journal of Internal Medicine·L I Shlush, T Feldman
Jun 9, 2021·Nature Communications·Erwin M SchoofBo T Porse
Aug 4, 2021·Cell Stem Cell·Laura García-PratJohn E Dick
Dec 31, 2021·PLoS Computational Biology·Phuc NguyenHao Yuan Kueh

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