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

Abstract

Induced pluripotent stem (iPS) cells provide powerful tools for studying disease mechanisms and developing therapies for diseases. The 8p11 myeloproliferative syndrome (EMS) is an aggressive chronic myeloproliferative disorder (MPD) that is caused by constitutive activation of fibroblast growth factor receptor 1. EMS is rare and, consequently, effective treatment for this disease has not been established. Here, iPS cells were generated from an EMS patient (EMS-iPS cells) to assist the development of effective therapies for EMS. When iPS cells were co-cultured with murine embryonic stromal cells, EMS-iPS cells produced more hematopoietic progenitor and hematopoietic cells, and CD34+ cells derived from EMS-iPS cells exhibited 3.2–7.2-fold more macrophage and erythroid colony forming units (CFUs) than those derived from control iPS cells. These data indicate that EMS-iPS cells have an increased hematopoietic differentiation capacity, which is characteristic of MPDs. To determine whether a tyrosine kinase inhibitor (TKI) could suppress the increased number of CFUs formed by EMS-iPS-induced CD34+ cells, cells were treated with one of four TKIs (CHIR258, PKC 412, ponatinib, and imatinib). CHIR258, PKC 412, and ponatinib reduced the number of CFUs formed by EMS-iPS-induced CD34+ cells in a dose-dependent manner, whereas imatinib did not. Similar effects were observed on primary peripheral blood cells (more than 90% of which were blasts) isolated from the patient. This study provides evidence that the EMS-iPS cell line is a useful tool for the screening of drugs to treat EMS and to investigate the mechanism underlying this disease.

Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models

“…Nonetheless, this frequency exceeds many other genetic events seen in AML. Overexpression of FGFR1 is also the driver of SCLL, which is similarly sensitive to anti-FGFR1 therapies [18, 36–38]. The presence of FGFR1 overexpression in these AML, however, was confirmed using quantitative PCR, unlike those in the databases.…”

Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement

“…Recently, the third‐generation TKI ponatinib has been demonstrated to inhibit phosphorylation levels of various FGFR1‐fusion kinases and their downstream effector functions, resulting in cell growth inhibition and cell death in vitro . Induced pluripotent stem cells generated from a patient with EMS with CEP110‐FGFR1 formed reduced colony‐forming unit numbers when treated with CHIR258 (dovitinib), PKC 412 (midostaurin), and ponatinib, but not with imatinib, and similar effects were observed in vitro for this patient's blood cells . Finally, a partial response to ponatinib has recently been reported in a 47‐year‐old patient with BCR‐FGFR1 ‐positive mixed‐phenotype leukemia who was subsequently rescued with repeat inductions with methotrexate and cytarabine followed by allogeneic HCT .…”

Precursor T-Lymphoblastic Lymphoma Associated with t(8;9)(p11.2;q33): A Case Report and Review of the Literature

“…Dovitinib (CHIR258, TKI258) is a multitarget receptor tyrosine kinase inhibitor with activity against class III, IV, and V receptor tyrosine kinases, such as VEGFRs, FGFRs, PDGFRs, FLT3, KIT, and CSF-1R. This molecule is currently being tested in a phase III clinical trial for renal cell carcinoma, and phase II clinical trials for advanced breast and endometrial cancers, relapsed multiple myeloma, and urothelial cancer [31]. Studies assessing MYM2-FGFR1-or BCR-FGFR1-transformed Ba/F3, KG1, and KG1A AML cell lines (FGFR1OP2-FGFR1) as well as primary cells from EMS patients demonstrated that TKI258 inhibits cell proliferation at low nanomolar concentrations [32,33].…”