By using stem cells to create laboratory models of an uncommon type of blood cancer which typically affects children under the age of six, researchers are hoping to learn more about the mechanisms behind the disease as well as the factors that influence its severity.
As part of their “leukemia in a dish” research, doctors from the Mount Sinai Hospital and the Mount Sinai School of Medicine engineered stem cells to investigate juvenile myelomonocytic leukemia (JMML), which is often triggered by inherited changes in the DNA code for the gene PTPN11 and the resulting development of a genetic disease called Noonan syndrome.
Currently, the only treatment for JMML involves replacing the hematopoietic stem cells that become blood cells through a bone marrow transplant. However, the procedure only works about half of the time, and the Mount Sinai team was hoping that by finding out more about the disease, how it develops and how it grows, they could discover better treatments for it.
“Our study clarified early events in the development of one kind of leukemia,” corresponding author Dr. Bruce D. Gelb, Director of The Mindich Child Health and Development Institute in the Icahn School of Medicine at Mount Sinai, explained Thursday in a statement.
“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. The work also provided new targets for the field to develop new drugs against in JMML,” he added.
Severity of JMML linked to degree of genetic changes
Often when researchers are hoping to gain new insight into genetic diseases, they take skin cells from patients with the condition, then use enzymes to coax cells back along the differentiation pathway to become induced pluripotent stem cells (iPSCs), the authors claimed.
These stem cells can be programmed to mature into cells, including hematopoietic (blood) cells, which are used to recreate a unique version of each patient’s genetic disease in a petri dish for further analysis. In the new study, which was published in the journal Cell Reports, Dr. Gelb and his team used this technique to create blood cells from iPSCs with PTPN11 mutations.
They found that these cells actually do behave like the actual cells found in the JMLL patients themselves, and that the “gain of function” genetic changes which cause this protein’s expression to increase were capable of causing leukemia-related changes in the cells. By doing so, they were able to determine that not all forms of JMML are identical, which could help treatment.
“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. “These findings provide a toe-hold in efforts to design specific treatments for this form of the disease.”
“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,” he added. “These proteins promise to become a focus of future drug design efforts.”
—–
Image credit:
Comments