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.
Highlights
chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of predominantly myeloid cells, and their subsequent accumulation in the bone marrow and peripheral blood
We generated transgene-free induced pluripotent stem cells (iPSCs) from the bone marrow mononuclear cells of a patient with a newly diagnosed CML in the chronic phase (CML15 iPSCs and CML17 iPSCs) and showed that these iPSCs capture the entire genome of neoplastic cells, including the unique 4-way translocation between chromosomes 1, 9, 22, and 11 that was present in the patient bone marrow (BM) (Hu et al, 2011)
Since we previously found that cells with such features can be generated from karyotypically normal iPSCs by coculture with OP9 (Choi et al, 2009a; Choi et al, 2009b; Vodyanik et al, 2005), we used this system to induce hematopoietic differentiation from CML iPSCs
Summary
CML is a myeloproliferative disorder characterized by unregulated growth of predominantly myeloid cells, and their subsequent accumulation in the bone marrow and peripheral blood. Ex vivo cultures of CML-derived cell lines and primary CML cells, ectopic expression of BCR-ABL in CD34+ cells and mouse models have provided important insights into CML pathogenesis and led to the development of targeted therapy for this neoplastic disease with BCR-ABL tyrosine kinase inhibitor (TKI), imatinib (Druker et al, 2006; Druker et al, 2001) Despite these achievements, eradication of CML remains challenging. We tested the hypothesis that reprogramming CML cells to pluripotency and differentiating them back into blood cells can be used as a novel approach to produce an unlimited number of primitive hematopoietic cells with LSC properties and identify novel primitive leukemia cell survival factors and drug targets We validated this hypothesis by demonstrating the successful application of the iPSC-based platform to discover OLFM4 as a novel primitive leukemia cell survival factor in patients in the chronic phase of CML. This finding provides a basis for development of novel approaches for treating CML by targeting OLFM4 or OLFM4-mediated signaling pathways in primitive leukemia cells
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