Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

ABSTRACT

Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology.

Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription.

Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

KEYWORDS:

• Epigenetic target
• hematopoietic cancer
• MPN
• mutational landscape
• PTCL
• therapeutic target

Article highlights

• MPN and PTCL are both aggressive hematopoietic malignancies, requiring targeted treatment.

• High occurrence of resistance mechanisms in MPN patients limits effective use of Ruxolitinib in clinics.

• Treatment options for PTCL patients are limited to chemotherapy due to a lack of potential molecular targets for this disease.

• High mutational rates in epigenetic regulators, as well as other common signaling pathways, have been reported in both MPN and PTCL.

• Potential strategies to improve treatment of both MPN and PTCL patients include drugs targeting these commonly mutated pathways.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

B. Wingelhofer, H. A. Neubauer, B. Maurer, and R. Moriggl are supported by the Austrian Science Fund (FWF) [SFB-F4707-B20, SFB-F06105, SFB-F06107]. P. Valent is supported by FWF SFB-F4704-B20. A. Orlova is supported by the Austrian Research Promotion Agency [FFG, 854452]. G. M. Keserü is supported by the Hungarian Scientific Research Fund [OTKA, K116904]. A. Berger-Becvar and P. T. Gunning are sponsored by CIHR, Canada Foundation for Innovation [497203, 495468], a Tier II Canada Research Chair, a MITACS fellowship and the Leukemia Lymphoma Society [IT05960].