How MPNs progress to AML and how to stop it
Thrive Award Spotlight:
John Crispino, St. Jude Children's Research Hospital
Co-PI - Ayalew Tefferi, Mayo Clinic, MN Aberrant Megakaryopoiesis in the MPNs
According to Leukemia & Lymphoma Society, although MPN patients can be stable for decades, they face a significant risk of having their disease advance to a more immediately life-threatening blood cancer, acute myeloid leukemia (AML). Approximately 10-20 % of myelofibrosis (MF) patients will progress to AML, for which the only current, potentially curative therapy is stem cell transplantation*.
This underscores the critical need to better understand how and when this transition occurs, “with a goal of treating and even preventing progression,” according to John Crispino, PhD, of St. Jude Children’s Research Hospital.
He explains his collaborative research with colleagues in Oxford, UK and the study funded by MPN Research Foundation through a 2022 Thrive award.
“We are focusing on a chromosome 21 gene named DYRK1A as a candidate driver of AML. Together, we have discovered that amplification of the DYRK1A gene is a relatively common event in progression of the MPNs to AML.” Collaborators include Drs. Charlotte Brierly, Adam Mead, and Beth Psaila.
“DYRK1A contributes to disease evolution through regulation of JAK/STAT signaling, cell death and DNA damage repair,” Dr. Crispino explains. “We predict that inhibiting DYRK1A may provide a new path for treating the AML phase of the MPNs and are initiating pre-clinical studies to test the effects of DYRK1A inhibitors in models of post-MPN AML.”
The research that Drs. Crispino and Tefferi perform is aimed at understanding how cells called megakaryocytes contribute to MPNs and to leukemia progression. Megakaryocytes make platelets that are essential to control bleeding.
In its simplest form, “We use advanced laboratory techniques to study the changes in megakaryocytes that occur during disease progression and hope that our discoveries lead to new cures,” says Dr. Crispino.
About 15 years ago, while on the faculty at Northwestern University, Dr. Crispino served on a grant review panel for MPN Research Foundation. MPNRF’s founders, Bob Rosen and Barbara Van Husen, asked him to act as the organization’s first scientific advisor. He remains a valued member of the Scientific Advisory Board today.
“Becoming friends with Bob and Barbara was a powerful force that further propelled my interest in the MPNs, an interest that continues to this day,” he says. “Bob’s passing from complications related to post-MPN AML has had an enormous impact on the way I think of this disease and highlights the urgency to develop new treatments.”
- • The Crispino lab has long focused its research efforts on the biology of the megakaryocytes (MK), the blood cell that produces platelets.
- • A key feature of MPNs is the over production of MKs in essential thrombocythemia (ET) and expansion of atypical MKs that contribute to fibrosis in myelofibrosis (MF).
- • A major goal of the lab is to better understand the factors that drive MPN MKs toward acute myeloid leukemia and to develop strategies to prevent or slow disease progression.
- • This project focuses on a novel signaling axis called DYRK1A-NFAT as a key controller of aberrant MK production.
- • The ultimate goal is to use this new information to develop therapeutic agents/strategies to prevent or inhibit aberrant MKs development and progression to MF.
* “What are Myeloproliferative Neoplasms | LLS”, Leukemia & Lymphoma Society, www.lls.org/research/myeloproliferative-neoplasms-mpn-research-funded-lls.