Regulation of human hematopoietic stem cell self-renewal by the microenvironment's control of retinoic acid signaling.

The high expression of aldehyde dehydrogenase 1, also known as retinaldehyde dehydrogenase, by hematopoietic stem cells (HSCs) suggests an important role for retinoic acid (RA) signaling in determining the fate of these cells. We found that primitive human bone marrow-derived CD34(+)CD38(-) cells not only highly express aldehyde dehydrogenase 1, but also the RA receptor α. Despite the up-regulation of early components of RA signaling, the downstream pathway remained inactive in the primitive CD34(+)CD38(-) cells. Primitive hematopoietic cells rapidly undergo terminal differentiation when cultured away from their microenvironment; however, we found that inhibition of RA signaling maintained their primitive phenotype and function, and promoted their self-renewal. HSCs reside in a complex microenvironment that enforces the balance between self-renewal and differentiation. The exact physiologic mechanisms by which the niche controls HSC fate remain elusive. The embryonic gonadal microenvironment has recently been shown to determine germ-cell fate by degrading RA through expression of the P450 retinoid-inactivating enzyme CYP26B1. We found that the bone marrow microenvironment similarly can control primitive hematopoietic cell fate via modulation of retinoid bioavailability. Accordingly, we found that bone marrow stromal cell CYP26 was also able to inactivate retinoids in serum, preventing RA signaling. Thus, primitive hematopoietic cells appear to be intrinsically programmed to undergo RA-mediated differentiation unless prevented from doing so by bone marrow niche CYP26. Modulation of RA signaling also holds promise for clinical HSC expansion, a prerequisite for the wide-scale use of these cells in regenerative medicine and gene therapy.

Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations.

The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (MYCN, TIMELESS); downregulation of pro-differentiation and TGF-ß/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g., CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication these cells and achieve cure.