Personal tools
You are here: Home Administration Chemistry & Biochemistry Department Events 2018 February Biochemistry Seminar: Julie-Aurore Losman, MD, PhD, "Epigenetic targets of R-2HG in IDH mutant AML"

Biochemistry Seminar: Julie-Aurore Losman, MD, PhD, "Epigenetic targets of R-2HG in IDH mutant AML"

Julie-Aurore Losman, MD, PhD, Asst Prof of Medicine, Harvard Medical Sch and Medical Oncology, Dana-Farber Cancer Institute, Harvard, "Epigenetic targets of R-2HG in IDH mutant AML"
When Feb 28, 2018
from 12:00 PM to 01:00 PM
Where CUNY ASRC Main Auditorium
Contact Name
Contact Phone 212-650-8803
Add event to calendar vCal
iCal

ABSTRACT

Oncogenic mutations in Isocitrate Dehydrogenase (IDH) are present in a wide range of cancers, including Acute Myeloid Leukemia (AML). These mutations alter the catalytic activity of IDH such that, instead of converting isocitrate to 2-oxoglutarate (2OG), the mutant enzymes convert 2OG to R-2-hydroxyglutarate (R-2HG), a metabolite that is normally found at very low levels in cells but that accumulates to millimolar levels in IDH mutant cells. 2OG plays a central role in cellular metabolism, both as a TCA cycle intermediate and as a co-factor for a number of important metabolic and epigenetic enzymes. There are ~70 2OG-dependent dioxygenases in the human genome, including Jumonji-domain-containing histone lysine demethylases and TET DNA hydroxylases. Given the high concentration of R-2HG in IDH mutant cells, and given the structural similarly between 2OG and R-2HG, it is hypothesized that R-2HG promotes cellular transformation by dysregulating one or more of these 2OG-dependent enzymes.

The 2OG-dependent myeloid tumor suppressor TET2 is the most well-validated direct target of R-2HG in cancer. TET enzymes catalyze the hydroxylation of 5-methylcytosine (5-mC) to produce 5-hydroxymethylcytosine (5-hmC), and mutant IDH cells are characterized by marked global loss of 5-hmC. TET2, like IDH, is recurrently mutated in clonal myeloid disorders, but IDH mutations and TET2 mutations are mutually exclusive in AML. This observation strongly suggests that mutant IDH and loss of TET2 have redundant mechanisms of transformation. However, TET2 and IDH mutations also appear to have distinct effects in cells. We hypothesize that these distinct characteristics of IDH mutant AML are due to dysregulation of other 2OG-dependent enzymes by R-2HG, and that these other putative targets of R-2HG play a role in mutant IDH-mediated transformation. In order to identify other, non-TET2, tumor suppressor targets of R-2HG, we have designed an sgRNA library that targets all known 2OG-dependent enzymes, as well as a number of other epigenetic enzymes, and have performed a positive selection screen to identify genes whose loss promotes cellular transformation. I will discuss the results of this screen and our on-going efforts to determine whether these candidate R-2HG targets do, in fact, play a role in mutant IDH-mediated transformation.

 

More information about this event…