Michael Rehli • Dept. Internal Medicine III • University Hospital • F.-J.-Strauss Allee 11 • 93053 Regensburg
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JournalClub

Donnerstags 9.00 Uhr 14-tägig
im Seminarraum Forschungsbau H1

nächster Termin: 05th October 2017


Proudly presented by: Karina M. (AG Rehli)

Restoration of TET2 Function Blocks Aberrant Self- Renewal and Leukemia Progression

Cimmino et al.

Cell 170, 1079-1095

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethy lation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a cofactor of Fe2+ and a-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.


Weitere Termine:

N.N.
21. September 2017
Karina M. (AG Rehli)
05. October 2017
David D. (AG Rehli)
19. October 2017
Christina B. (AG Kreutz)
09. November 2017
Laura K. (AG Thomas)
23. November 2017
Jan B. (AG Rehli)
07. December 2017
Sonja D. (AG Kreutz)
14. December 2017


updated on 23rd August 2017

 
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