Scientists from the Children’s Hospital of Philadelphia say they have got found how mutations in a protein network drive many high-risk leukemias,   particularly chronic myelomonocytic leukemia (CMML) and  juvenile myelomonocytic leukemia  (JMML), both of which generally have a poor prognosis as they progress to  acute myeloid leukemia  (AML).   An existing drug might be repurposed to treat these types of leukemias, and the new understanding of the molecular mechanisms at the job may offer clues to other drugs yet to be created, according to that investigators.  

A group at  Children’s Hospital of Philadelphia  (CHOP), reveals exactly how mutated proteins cause several types of leukemia,   “These leukemias currently have few treatment options, so identifying the causative gene networks may lead to more effective targeted treatments, ” said    Wei Tong, Ph. D., a  hematology  researcher in whose team published its study (“CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoetic stem cells and myeloid malignancies”  Genes”)  in Genes and Development.

The group researched a well-known kinase, JAK2, which plays a key part in the development of blood-forming cells in bone marrow. In the event that something disrupts the normal regulation of JAK2 activity, JAK2 triggers the uncontrolled growth of marrow cells that provide rise to a myeloid leukemia. Until now, the molecular activities that regulate JAK2 were poorly established.

Based on studies in animals and in primary human leukemia cells, Dr . Tong and colleagues report that variations in either of two proteins, CBL and LNK/SH2B3, form a complex with JAK2 to disrupt JAK2 regulation and cause leukemia.

“This studies have major implications for leukemia patients, ” said Doctor Tong. “A drug called ruxolitinib inhibits JAK2 and it is already approved by the Food and Drug Administration. Our research in cells from leukemia patients strongly suggest that sufferers with mutations in any of the three proteins could take advantage of ruxolitinib. ” 

Dr . Tong added that will clinical research should test whether this drug can benefit sufferers with CMML and JMML, as well as AML patients who may have CBL mutations.

In addition to the potential benefits of ruxolitinib, she continued, the team’s findings may lead scientists to develop novel leukemia drugs aimed at mutations in any from the three proteins in a precision medicine approach. “As we all continue to discover that specific mutations may cause subtypes of malignancy, learning the underlying molecular mechanisms provides opportunities to develop focused treatments. ”