Targeting the JAK2V617F Hematopoietic Stem Cell Through Integrins-Based Combination
Advancing Research: Targeting the JAK2V617F Hematopoietic Stem Cell Through Integrins-Based Combination
Early in her career, as a veterinarian, Shinobu Matsuura, DVM, PhD, remembers a debilitating case of aplastic anemia in a young German shepherd. It pulled on her heart strings and solidified her belief that bone marrow is the most important organ in the body.
Today in her research lab, she sees the management of JAK2 inhibitor resistant cases as one of the biggest challenges in (human) MPN treatment – particularly addressing worsening fibrosis (scarring in the bone marrow) and malignant transformation.
According to Dr. Matsuura, the most likely source of these conditions is the JAK2V617F hematopoietic stem cell (HSC) clones that accumulated mutations over time, acquiring an aggressive and leukemic set of characteristics (phenotype).
“The goal of my research is to specifically reduce or eliminate those clones before they have the opportunity for malignant transformation,” she says, “which I believe is the key for the long-term management of MPNs.” Her work has been funded through a 2022 Thrive Initiative Junior Investigator award.
The project investigates a way of moving beyond MPN therapies that mostly improve blood parameters and symptoms. It is based on a stunning discovery that inhibiting integrin, a molecule used by cells for attachment to their environment, was able to decrease the number of malignant JAK2V617F-mutated HSCs in mice – without affecting normal stem cells.
Reducing malignant HSCs would be a therapeutic breakthrough because they are the source of all mutated blood cells. They are also believed to be responsible for disease relapse and transformation to acute myeloid leukemia.
“If this project is successful, we will be taking the first step in the development of anti-integrin therapy, capable of eliminating only the JAK2V617F malignant hematopoietic stem cells, without affecting normal cells,” says Dr. Matsuura. “I believe that if the proposed experiments are successful, we will be on the way to develop a drug that may truly make a difference.”
- • Mutated MPN hematopoietic stem cells, e.g., with a JAK2V617F mutation, are the primary driver of MPN disease initiation and progression.
- • The greatest patient concerns go beyond daily control of symptoms and the potential for thrombotic events, to preventing their disease from progressing to more advanced and life-threatening forms of MPNs.
- • Most therapeutic regimens available today do not selectively eliminate the mutated MPN stem cell (interferon being the exception in some patients).
- • This study is focused on a protein called beta 1 integrin which shows elevated activation on JAK2 mutated stem cells, versus normal cells.
- •The goal of this project is to determine if the therapeutic use of the anti-beta 1 integrin antibody can lead to complete MPN stem cell exhaustion (with potentially curative implications) and be a viable and safe therapy.