Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells

Abstract

A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia cells, we discovered olfactomedin 4 (OLFM4) as a novel factor that contributes to survival and growth of somatic lin−CD34+ cells from bone marrow of patients with CML in chronic phase, but not primitive hematopoietic cells from normal bone marrow. Overall, this study shows the feasibility and advantages of using reprogramming technology to develop strategies for targeting primitive leukemia cells.

Aberrantly expressed transcription factors C/EBP and SOX4 have positive effects in the development of chronic myeloid leukemia

“…The mutation or deletion of C/EBPα may result in arrest of the transit of common myeloid progenitors into granulocyte-monocyte progenitors, and lead to a reduction in granulocytes and monocytes (22). In addition, deficiency of C/EBPα in mice may induce disorder in myeloproliferation (19). In the present study, significantly lower expression of C/EBPα was detected in patients with CML, compared with that in normal controls.…”

“…CML is a myeloproliferative disorder originating from hematopoietic stem cells with constitutive expression of the BCR/ABL oncoprotein (19). Imatinib was the first target drug approved by the US Food and Drug administration for the treatment of CML, and remains a commonly used drug in clinical therapy (20).…”

Generating human hematopoietic stem cells in vitro –exploring endothelial to hematopoietic transition as a portal for stemness acquisition

“…Our studies have revealed that hematopoietic progenitors within the CD34 + cell population in human PSC cultures could be precisely identified based on the expression of leukosialin (CD43), that reliably separates them from CD43 − CD31 + endothelial cells and CD43 − CD31 − cells with mesenchymal characteristics . CD34 + CD43 + PSC‐derived progenitors are composed of two major populations: (a) erythromegakaryocytic progenitors that coexpress CD235a and CD41a, and (b) CD235a − CD41a − CD43 + CD45 +/− multilineage progenitors that are lacking lineage markers and display CD90 + CD117(c‐kit) + CD38 − CD45RA − phenotype typical for human HSCs emerging in AGM (Fig. ).…”

“…). The PCS‐derived lin − CD34 + CD43 + CD45 +/− CD117 + CD90 + CD38 − CD45RA − population possesses CFC potential similar to cord blood lin − CD34 + CD38 − cells , LTC‐IC potential, a high ALDH activity, the ability to efflux rhodamine‐123, and is able to differentiate into all types of myeloid cells and lymphoid cells . Recent studies also demonstrated that hESC‐derived CD34 + CD38 −/low CD90 + CD45 + hematopoietic cells express GPI‐80, a marker of human fetal liver HSCs .…”

“…Alternatively, the generation of gene‐targeted iPSC lines with only a single clonal event can be achieved using simultaneous reprogramming and CRISPR/Cas9 gene editing in somatic cells . In addition, reprogramming nonhematopoietic somatic and mature blood cells to pluripotency and their subsequent differentiation into hematopoietic stem cells/progenitors offers a promising tool for modeling blood diseases , studying primitive leukemia cells , and drug discovery . However, de novo generation of blood cells with robust multilineage engraftment potential from human PSCs (iPSCs and embryonic stem cells; ESCs) remains a significant challenge .…”