Our Science – Wolff Website
Linda Wolff, Ph.D.
The focus of the research is on the development of murine acute myeloid leukemia (AML) models using retroviruses and on the role of specific oncogenes and tumor suppressors in leukemia.
INK4b tumor suppressor
The p15INK4b gene is member of a family of cyclin dependent kinase inhibitors that prevent G1/S transition at the restriction point involving the RB pathway. The gene is upregulated in response to cytokines that induce differentiation and/or growth arrest. Importantly, it plays a significant role in hematopoietic neoplasia, since it is inactivated by hypermethylation in more than 80% of acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). The lab has developed murine models in which targeted deletion of the gene can accelerate retrovirus-induced myeloid leukemia. Mice deficient in p15Ink4b are also being used to study the role of the gene in development of the myeloid cell compartment and homeostasis. In additional studies we are investigating the mechanisms involved in the transcriptional repression of the p15Ink4b promoter in leukemia.
The c-myb oncogene
The c-myb is essential for the development of hematopoietic cells and plays a role in proliferation, anti-apoptosis and differentiation. We have discovered that the c-myb can be activated to transform myeloid cells either by overexpression at the transcriptional level or by protein truncation which removes sequences that are critical for phosphorylation-induced ubiquitinization and 26S-proteasome degradation. In other studies, we have identified important target genes that c-Myb, a transcription factor, regulates and that are involved in mediating its transforming function in cells. c-Myb directly transactivates c-myc, a critical component in control of proliferation, and Bcl-2, an inhibitior of programmed cell death. Recently the laboratory has shown that c-Myb also inhibits expression of the tumor suppressor and cdk inhibitor, p15INK4b.
This page was last updated on 3/12/2014.