The JAK-STAT signaling pathway is an important pathway in malignant transformation. On the basis of these observations, JAK2 kinase inhibitors have been developed for clinical use, and ruxolitinib, a JAK2/JAK1 inhibitor is approved for primary myelofibrosis. More importantly, different JAK2 inhibitors have entered clinical trials for use in chronic myeloid leukemia (CML), acute lymphoblastic T-cell leukemia and myelodysplastic syndrome patients. Recent studies even have suggested a role for JAK2 kinase inhibition for patients with breast cancer, lung cancer and pancreatic tumors and clinical trials are evaluating the role of JAK2 inhibitors in epithelial tumors.
Although there is a strong rationale for JAK2 kinase inhibition in JAK2-mutant malignancies to date, these agents have not led to molecular or pathologic remissions at clinically achievable doses. As such, there is a need to better delineate the therapeutic window of JAK2 kinase inhibition and to better understand the requirement for JAK2 signaling in normal tissue homeostasis and in different malignant contexts.
Therefore researchers with support of Florian Grebien from the LBI-CR have now explored the function of Jak-2 in the hemtopoietic stem cell (HSC) compartment and found the loss of this crucial signal transducer to result in a reduced number of HSCs in the bone marrow of transgenic mice and a selective disadvantage in competitive transplantations. Taken together, with other data recently reported in Leukemia, the authors demonstrate a critical role for JAK2 for HSC maintenance, survival and function. In summary, JAK2 has a critical role in normal hematopoiesis, and current and future therapeutic approaches aimed at targeting JAK2 need to consider effects on stem cell function and the relative inhibitory effects on normal and malignant cells, which might limit, or even abrogate, therapeutic use of JAK2 inhibitors.
This research was recently published in Leukemia