Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells.

Abstract:

:Chronic myeloid leukemia (CML) originates in a hematopoietic stem cell (HSC) transformed by the breakpoint cluster region (BCR)-abelson (ABL) oncogene and is effectively treated with tyrosine kinase inhibitors (TKIs). TKIs do not eliminate disease-propagating leukemic stem cells (LSCs), suggesting a deeper understanding of niche-dependent regulation of CML LSCs is required to eradicate disease. Cxcl12 is expressed in bone marrow niches and controls HSC maintenance, and here, we show that targeted deletion of Cxcl12 from mesenchymal stromal cells (MSCs) reduces normal HSC numbers but promotes LSC expansion by increasing self-renewing cell divisions, possibly through enhanced Ezh2 activity. In contrast, endothelial cell-specific Cxcl12 deletion decreases LSC proliferation, suggesting niche-specific effects. During CML development, abnormal clusters of colocalized MSCs and LSCs form but disappear upon Cxcl12 deletion. Moreover, MSC-specific deletion of Cxcl12 increases LSC elimination by TKI treatment. These findings highlight a critical role of niche-specific effects of Cxcl12 expression in maintaining quiescence of TKI-resistant LSC populations.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

Agarwal P,Isringhausen S,Li H,Paterson AJ,He J,Gomariz Á,Nagasawa T,Nombela-Arrieta C,Bhatia R

doi

10.1016/j.stem.2019.02.018

subject

Has Abstract

pub_date

2019-05-02 00:00:00

pages

769-784.e6

issue

5

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(19)30070-0

journal_volume

24

pub_type

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