Researchers have uncovered how mutations in a protein network drive several high-risk leukemias, offering new prospects for novel therapies. In a report published online
on June 13 in Genes and Development
, researchers from Children’s Hospital of Philadelphia identified some of the causative gene networks that point the way toward more effective targeted treatments.
The researchers demonstrated how mutated proteins in chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) progress to acute myeloid leukemia (AML). It turns out that a drug already commercially available may be a new tool against both CMML and JMML.
Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs); if something disrupts the normal regulation of JAK2 activity, JAK2 triggers the uncontrolled growth of marrow cells and subsequently leads to myeloid leukemia. Until now, the molecular events that regulate JAK2 were poorly established. Based on studies in animals and in primary human leukemia cells, the researchers now report that mutations in either of two proteins, CBL and LNK/SH2B3, form a complex with JAK2 to disrupt JAK2 regulation and cause leukemia.
“CBL mutations are found in a wide range of myeloid malignancies with the most frequent occurrence in chronic and juvenile myelomonocytic leukemia (CMML and JMML), which bear poor prognosis with propensity for progression to acute leukemia. Our work identified JAK2 as a relevant therapeutic target of CBL,” said study investigator Wei Tong, PhD, a hematology researcher at Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
She said CBL-mutated AMLs are hypersensitive to the JAK2 inhibitor ruxolitinib, which is already approved by the Food and Drug Administration (FDA). Ruxolitinib phosphate was approved by the FDA in November 2011 for treating intermediate- and high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Tong said JAK inhibitors alone will not likely cure AML or CMML/JMML; however, she said these findings have significant clinical implications for leukemia patients.
The research team found that CBL-mutated AMLs are not only more sensitive to ruxolitinib, but also perhaps other JAK inhibitors. Tong said these new findings support the notion that JAK inhibitors should be tested in patients with CMML, JMML, and other types of myeloid leukemias with CBL mutations. She and her colleagues now plan follow-up studies that will help better elucidate the genetic mutations that may be driving many myeloid leukemias.
“We plan to dissect CBL signaling network in HSPCs and myeloid leukemia, using both genetics and proteomics approaches,” Tang told OncoTherapy Network. “We hope to identify novel therapeutic targets of CBL that synergize with JAK inhibition and/or current therapies in treating CBL-mutated myeloid leukemias. Furthermore, we plan to screen for novel regulators of JAK2 that determine its stability, signaling, and activity.”