Image from the Salk Institute
Researchers have used induced pluripotent stem cells (iPSCs) to model juvenile myelomonocytic leukemia (JMML) and gain new insight into the disease.
The team noted that somatic PTPN11 mutations are known to cause JMML, germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML.
With their work, the researchers found that hematopoietic cells differentiated from iPSCs harboring NS/JMML-causing PTPN11 mutations recapitulate the features of JMML.
They described this work in Cell Reports.
“By studying an inherited human cancer syndrome, our study clarified early events in the development of [JMML],” said Bruce D. Gelb, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“More than just creating a model of a disease, we were able to prove that mechanisms seen in our model also happen in the bone marrow of people with this kind of leukemia.”
Specifically, the team found that NS/JMML myeloid cells derived from iPSCs demonstrated increased signaling through STAT5 and upregulation of 2 microRNAs—miR-223 and miR-15a.
Likewise, miR-223 and miR-15a were upregulated in 11 of 19 bone marrow samples from patients with JMML harboring PTPN11 mutations.
However, the microRNAs were not upregulated in patients without PTPN11 mutations. And when the researchers reduced miR-223’s function in NS/JMML iPSCs, they observed a normalization of myelogenesis.
“Going into the current study, experts in the field had tended to lump all forms of JMML together, but the new study was able to isolate biological changes specific to hematopoietic cells with PTPN11 mutations, which causes more severe JMML,” Dr Gelb said.
He and his colleagues also found that microRNA target gene expression levels were reduced in the iPSC-derived myeloid cells and in cells from JMML patients with PTPN11 mutations.
“Our results provide further evidence that the severity of this form of leukemia arises from the degree of changes in the gene PTPN11, altering the protein it codes for, SHP-2, and biologic pathways related to it,” Dr Gelb said. “These proteins promise to become a focus of future drug design efforts.”
