Featuring: Peng Ji, MD, PhD, ‘15 GME
Investigators have discovered that a specific complex drives cell proliferation in different forms of blood cancers called mutated myeloproliferative neoplasms (MPNs), suggesting the complex could serve as an ideal therapeutic target, according to a Northwestern Medicine study published in the Journal of Clinical Investigation.
“This paper has set up a stepping stone for future drug development for patients with MPNs,” said Peng Ji, MD, PhD, ‘15 GME, professor of Pathology in the Divisions of Experimental Pathology and Hematopathology, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and senior author of the study.
MPNs occur when mutated stem cells in the bone marrow cause an overproduction of white cells, red cells and platelets. According to the Leukemia and Lymphoma Society, an estimated 100,000 people in the U.S. currently live with or are in remission from MPNs.
Patients with MPNs have increased risk of thrombosis, such as stroke or heart attack, and increased risk of the disease evolving into different types of MPNs, such as myelofibrosis — when blood cell production is disrupted altogether — or in more severe cases, acute myeloid leukemia (AML) can occur when myeloid (bone marrow) cells interfere with blood cell production.
Current therapies for MPNs include chemotherapy and drugs which can help reduce the risk of thrombosis, however these therapies are ineffective to reduce thrombosis and disease progression. Adverse side effects also occur in patients who undergo extended therapy, underscoring the need for new therapies for MPNs, Ji said.
Previous work has established that MPNs contain a genetic mutation in the JAK2-STAT pathway, which contains the protein-encoding gene called JAK2 and drives other downstream target genes promoting pathogenesis. One of these genes is Pleckstrin-2 (Plek2), which Ji’s laboratory had previously discovered is overexpressed in patients with MPNs, making this gene an attractive therapeutic target.
In the current study, Ji’s team used high-throughput screening and cell-based assays to identify the precise mechanisms that Plek2 utilizes to mediate cell proliferation in JAK2-STAT mutated MPNs.
Using these techniques, they discovered that Plek2 is not only overexpressed by the JAK2-STAT pathway but also activates Akt — an essential protein kinase — and protects Akt from degradation, according to Ji.
“With the increase of Plek2, Akt will be hyperactivated, and Akt is important for cell proliferation. Therefore, this recruitment of Akt will drive cell proliferation in myeloproliferative diseases,” Ji said.
Based on this newly discovered mechanism, the investigators then used novel Plek2 small molecular inhibitors in mouse models of MPNs to block cellular signaling between Plek2 and Akt. The investigators administered either Plek2 inhibitors alone or in combination with an Akt inhibitor, discovering that both interventions demonstrated similar therapeutic efficacy to knocking out Plek2 in MPN cells in vivo.
The Plek2 inhibitors also reduced the proliferation of CD34 positive cells from MPN patients, which indicates similar efficacy in human cells.
“When Plek2 is overexpressed, it may induce cancer, but if you knock it out from the body, it doesn’t really matter since there are other compensatory mechanisms, so this really is an attractive target for the treatment of MPNs,” Ji said.
Xu Han, PhD, a postdoctoral fellow in the Ji laboratory, was lead author of the study. Co-authors include Rama Mishra, PhD, adjunct associate professor of Biochemistry and Molecular Genetics and Madina Sukhanova, PhD, assistant professor of Pathology in the Division of Cytogenetics and a member of the Lurie Cancer Center, Gary Schiltz, PhD, research professor of Pharmacology and a member of the Lurie Cancer Center, and Arabela Grigorescu, PhD, managing director of Northwestern University’s Keck Biophysics Facility.
Ji is also the founder of Aplexis, a startup that is developing novel therapies designed to treat MPNs and Plek2-overexpressing solid tumors.
This work was supported by National Institute of Diabetes and Digestive and Kidney Disease grant R01-DK124220, National Heart, Lung, and Blood Institute grant R01-HL148012, R01-HL150729, R01-HL148014, a Leukemia & Lymphoma Society Translational Research Grant and a Harrington Discovery Institute Scholar award.
This article was originally published in the Feinberg School of Medicine News Center on February 10, 2023.
Peng Ji, MD, PhD, ‘15 GME, professor of Pathology in the Divisions of Experimental Pathology and Hematopathology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was senior author of the study published in the Journal of Clinical Investigation.
Xu Han, PhD, a postdoctoral fellow in the Ji laboratory, was lead author of the study.
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