Variable Behavior of iPSCs Derived from CML Patients for Response to TKI and Hematopoietic Differentiation

Abstract

Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34+ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents.

Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency

“…However, reprogramming human primary cancer cells remains challenging, and only a few reports have demonstrated successful reprogramming of malignant cells. Moreover, iPSCs from primary leukemic cells have exclusively been generated from chronic hematological malignances, including Philadelphia + CML, PMF, JAK2-V617F + PV, and JMML ( Bedel et al., 2013 , Carette et al., 2010 , Gandre-Babbe et al., 2013 , Hu, 2014 , Kumano et al., 2012 , Yamamoto et al., 2015 , Ye et al., 2009 ) ( Table S1 ). No iPSCs reprogrammed from acute leukemias have been reported, but iPSCs have been successfully generated from normal myeloid, T cells, and B cells using non-integrative tetracistronic OKSM-expressing SeV ( Bueno et al., 2016 , Munoz-Lopez et al., 2016 ).…”

“…Reprogramming human primary cancer cells, however, remains challenging. Despite significant interest in generating iPSCs from leukemia cells ( Curry et al., 2015 , Ramos-Mejia et al., 2012c , Yilmazer et al., 2015 ), only a few reports have demonstrated successful reprogramming and, unfortunately, only seven of these studies reprogrammed human primary leukemias (the remaining studies used cell lines) ( Bedel et al., 2013 , Carette et al., 2010 , Gandre-Babbe et al., 2013 , Hu, 2014 , Kumano et al., 2012 , Yamamoto et al., 2015 , Ye et al., 2009 ) ( Table S1 ). Intriguingly, iPSCs from hematological primary cancer cells have exclusively been generated from chronic leukemias of myeloid origin, including Philadelphia + chronic myeloid leukemia (CML), primary myelofibrosis (PMF), JAK2-V617F + polycythemia vera (PV), and juvenile myelomonocytic leukemia (JMML) ( Table S1 ).…”

Screening of Drugs to Treat 8p11 Myeloproliferative Syndrome Using Patient-Derived Induced Pluripotent Stem Cells with Fusion Gene CEP110-FGFR1

“…We were only able to establish one EMS-iPS cell clone. In general, it is difficult to produce iPS cells from patients with hematologic malignancies [ 26 ], and only a few hematologic malignancy-specific iPS cell clones have been reported[ 27 – 31 ]. Owing to the rarity of EMS, the features of this disease are not fully understood.…”

“…The karyotype of t(8;9)(p12;q33) seemed to be original clone because of the only clone existed at diagnosis. Interestingly iPS cells already generated from hematologic malignancy had the feature of MPD in their background [ 27 – 31 ]. It is extremely difficult to establish iPS cells from patients with de novo acute leukemia.…”

Induced Pluripotent Stem Cells and Their Future Therapeutic Applications in Hematology

“…iPSCs were generated from primary CML patient samples [56,57]. The methylation pattern and the gene expression of CML-iPSCs were very similar to those with normal iPSCs [56].…”