TY - JOUR
T1 - Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms
AU - Saleiro, Diana
AU - Wen, Jeremy Q.
AU - Zannikou, Markella
AU - Lee, Brian
AU - Kosciuczuk, Ewa M.
AU - Nehlsen, Sarah D.
AU - Munshi, Adam
AU - Chen, Xintong
AU - Oku, Chidera V.
AU - Hryhorysak, Briana
AU - Guillen Magaña, Jamie N.
AU - Heneche, Jorge
AU - Fischietti, Mariafausta
AU - Ilut, Liliana
AU - Small, Sara H.
AU - Cotton, Anitria
AU - Hall, Trent
AU - Payton, Monique A.
AU - Beauchamp, Elspeth M.
AU - Yue, Feng
AU - Kocherginsky, Masha
AU - Bartom, Elizabeth T.
AU - Hoffman, Ronald
AU - Crispino, John D.
AU - Platanias, Leonidas C.
N1 - Publisher Copyright:
© 2025 Taylor & Francis Group, LLC.
PY - 2025
Y1 - 2025
N2 - Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in Jak2V617F-mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.
AB - Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in Jak2V617F-mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.
KW - ULK1
KW - myeloproliferative neoplasms
KW - signaling
KW - transcription regulation
UR - https://www.scopus.com/pages/publications/105011281129
U2 - 10.1080/10985549.2025.2529837
DO - 10.1080/10985549.2025.2529837
M3 - Article
C2 - 40697155
AN - SCOPUS:105011281129
SN - 0270-7306
VL - 45
SP - 395
EP - 418
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 9
ER -