Enhanced MAPK Signaling Proves an Essential Driver in CSF3R-induced Leukemia
Published August 31, 2017 | Leukemia
A two-pronged investigation into the mechanisms that drive the development of chronic neutrophilic leukemia (CNL) reveals the essential, and interconnected, roles of expressing protein and enhanced signaling.
CNL is a rare myeloproliferative neoplasm that affects peripheral blood, hepatosplenomegaly, and myeloid hyperplasia in bone marrow. Previous research has shown that CNL can be caused by both membrane-proximal and truncation mutations in the protein-coding gene colony stimulating factor 3 receptor (CSF3R).
Using whole-genome expression profiling, the team went further, demonstrating that the truncation mutation alone does not induce leukemia. Furthermore, proximal and compound mutations can induce the disease when located on the same allele.
That “ah-ha” finding occurred when researchers saw that induced expression of the MAPK adaptor protein Ksr1 and enhanced MAPK signaling were critical drivers of leukemia development in both mutants. A second revelation: inhibition of Mek1/2 by the cancer drug trametinib alone sufficiently suppressed leukemia in tests.
“We found out that the truncation mutation is not leukemogenic,” says lead investigator Mohammad Azam, PhD. “When expressed in the mice, nothing happened. It doesn’t cause leukemia. That was quite a surprise to me.”
Together, these findings point to a MAPK-dependent mechanism of CSF3R-induced pathogenesis, and establish a direct line for clinical evaluation of CNL. The team also involved the Division of Immunology. Azam said he benefited greatly from the insights of H. Leighton Grimes, PhD, Director of our Cancer Pathology Program.
“Once we know the drivers, we might be able to target them and predict benefit,” Azam says.
