Induced Pluripotent Stem Cells to Model Juvenile Myelomonocytic Leukemia: New Perspectives for Preclinical Research

Abstract

Juvenile myelomonocytic leukemia (JMML) is a malignant myeloproliferative disorder arising in infants and young children. The origin of this neoplasm is attributed to an early deregulation of the Ras signaling pathway in multipotent hematopoietic stem/progenitor cells. Since JMML is notoriously refractory to conventional cytostatic therapy, allogeneic hematopoietic stem cell transplantation remains the mainstay of curative therapy for most cases. However, alternative therapeutic approaches with small epigenetic molecules have recently entered the stage and show surprising efficacy at least in specific subsets of patients. Hence, the establishment of preclinical models to test novel agents is a priority. Induced pluripotent stem cells (IPSCs) offer an opportunity to imitate JMML ex vivo, after attempts to generate immortalized cell lines from primary JMML material have largely failed in the past. Several research groups have previously generated patient-derived JMML IPSCs and successfully differentiated these into myeloid cells with extensive phenotypic similarities to primary JMML cells. With infinite self-renewal and the capability to differentiate into multiple cell types, JMML IPSCs are a promising resource to advance the development of treatment modalities targeting specific vulnerabilities. This review discusses current reprogramming techniques for JMML stem/progenitor cells, related clinical applications, and the challenges involved.

Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

“…JMML research has been traditionally hindered due to its low incidence (1.2 cases per million children under 14 years of age), and the impossibility of maintaining primary JMML cells in vitro for extended periods of time or establishing immortalized JMML cells lines [ 123 , 124 ]. In this context, the development of methods to generate JMML patient-derived xenografts (PDX) and iPSCs has been instrumental to overcome low sample number difficulties and provide an unlimited source of JMML cells for experimental purposes.…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Hypersensitivity of JMML progenitors to GM-CSF, IL3 and TNFa in vitro, hyperproliferation of monocytic and/or granulocytic lineages in vivo, thrombocytopenia, and increased fetal hemoglobin (HbF in 50–60% of patients) are common JMML features, with occasional transformation to ALL, suggesting a disease of, or expressed in, multipotent HSC/MPP [ 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ]. A number of recent studies have investigated the cellular origin and clonal evolution of JMML using iPS cell [ 230 , 231 , 232 , 233 , 234 , 235 , 236 ] and xenograft models [ 237 , 238 , 239 ]. Caye et al [ 238 ] demonstrated the propagation of transplanted primary bone marrow JMML HSPCs (particularly those in the PTPN11, NRAS and KRAS subgroups and with a median age of 2.2 years) in immunodeficient NSG and NSG-SGM3 mice.…”

Are Induced Pluripotent Stem Cells a Step towards Modeling Pediatric Leukemias?

“…In fact, maintaining immature JMML progenitor cells in culture poses a big challenge, as they tend to differentiate and undergo rapid senescence. Indeed, it is possible to maintain undifferentiated JMML cells for approximately 2 weeks in medium supplemented with different types of cytokines [13]. Moreover, AML primary blasts are difficult to maintain in culture as well, due to rapid differentiation and undergoing apoptosis in ex vivo cultures, and they often need the bone marrow support or addition of small molecules such as Aryl hydrocarbon suppressor [14].…”