Abstract
Leukemic stem cells (LSCs) reside within bone marrow niches that maintain their relatively quiescent state and convey resistance to conventional treatment. Many of the microenvironmental signals converge on RAC GTPases. Although it has become clear that RAC proteins fulfill important roles in the hematopoietic compartment, little has been revealed about the downstream effectors and molecular mechanisms. We observed that in BCR-ABL-transduced human hematopoietic stem/progenitor cells (HSPCs) depletion of RAC2 but not RAC1 induced a marked and immediate decrease in proliferation, progenitor frequency, cobblestone formation and replating capacity, indicative for reduced self-renewal. Cell cycle analyses showed reduced cell cycle activity in RAC2-depleted BCR-ABL leukemic cobblestones coinciding with an increased apoptosis. Moreover, a decrease in mitochondrial membrane potential was observed upon RAC2 downregulation, paralleled by severe mitochondrial ultrastructural malformations as determined by automated electron microscopy. Proteome analysis revealed that RAC2 specifically interacted with a set of mitochondrial proteins including mitochondrial transport proteins SAM50 and Metaxin 1, and interactions were confirmed in independent co-immunoprecipitation studies. Downregulation of SAM50 also impaired the proliferation and replating capacity of BCR-ABL-expressing cells, again associated with a decreased mitochondrial membrane potential. Taken together, these data suggest an important role for RAC2 in maintaining mitochondrial integrity.
Highlights
Hematopoiesis is a hierarchical process, initiated by hematopoietic stem cells (HSCs) that reside within specialized regions of the bone marrow, termed the niche [1,2]
Over the past years it has become clear that RAC proteins fulfill important roles in the hematopoietic compartment, our insight into molecular mechanisms downstream of RAC1 and RAC2 is still limited
We show that BCR-ABL-transformed human hematopoietic stem/progenitor cells (HSPCs) critically depend on RAC2 for their proliferation and survival, which is linked to maintaining an appropriate mitochondrial integrity and mitochondrial membrane potential
Summary
Hematopoiesis is a hierarchical process, initiated by hematopoietic stem cells (HSCs) that reside within specialized regions of the bone marrow, termed the niche [1,2]. A constant crosstalk between an HSC and its microenvironment provides signals that maintain the HSC in a quiescent state and regulate its proliferation and differentiation, crucial both for the homeostasis of the hematopoietic system and stress hematopoiesis [3,4,5,6,7,8,9]. The hierarchical organization of the PLOS ONE | DOI:10.1371/journal.pone.0128585. Leukemic Stem Cells Depend on RAC2 collection and analysis, decision to publish, or preparation of the manuscript
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