Protein Network Signals Found to Drive Myeloid Leukemias

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

        The researchers at CHOP revealed 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 whose team published its study (“CBL Family E3 Ubiquitin Ligases Control JAK2 Ubiquitination and Stability in Hematopoietic Stem Cells and Myeloid Malignancies”) in Genes & Development.

        The group investigated a well-known kinase, Janus kinase 2 (JAK2), which plays a key role in the development of blood-forming cells in bone marrow. If something disrupts the normal regulation of JAK2 activity, JAK2 triggers the uncontrolled growth of marrow cells that give rise to a myeloid leukemia. Until now, the molecular events that regulate JAK2 were poorly established.

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        Based on studies in animals and in primary human leukemia cells, Dr. Tong and colleagues report that mutations in either of two proteins, Casitas B-cell lymphoma (CBL) and LNK/SH2B3, form a complex with JAK2 to disrupt JAK2 regulation and cause leukemia.

        “This research has major implications for leukemia patients,” said Dr. Tong. “A drug called ruxolitinib inhibits JAK2 and is already approved by the FDA. Our studies in cells from leukemia patients strongly suggest that patients with mutations in any of the three proteins could benefit from ruxolitinib.”

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

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