Role of Smad7 in myeloid leukemogenesis

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26830086
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: アーノ クズィーネ 公益財団法人がん研究会, その他部局等, 研究員 (70725621)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: Leukemia / TGF-beta / Smad7

Outline of Annual Research Achievements

Since in vivo inhibition of TGF-beta showed discrepant results on leukemisa onset, we sought to shed clarity onto the precise impact of TGF-beta on myeloid leukemic cells during in vivo propagation. For this purpose, we attempted to create leukemic cells knocked down for TGF-beta Receptor I or II to determine whether these cells are affected positively or negatively for the onset of leukemia. However, knocked down of TGF-beta Receptors was unsuccesfull and could not be achieved, although multiple tries were performed.
In parallele, new leukemic cells overexpressing Smad7 were created using a commercially available human Smad7 plasmid. However, these Hoxa9-Smad7-overexpressing cells inoculated into mice were unable to induce leukemia. Therefore, TGF-beta does not seem to have a major role on leukemic cells for the onset of the disease.

Since TGF-beta has other cellular targets than leukemic cells in vivo, particularly Tregs which are in turn TGF-beta producers, we investigated the role of these cells during leukemia. We found that Tregs depletion delayed the onset of leukemia, demonstrating that Tregs activity promotes leukemia onset, although moderately, presumably by immune system inhibition through TGF-beta production. However, when leukemic cells were co-incubated in vitro with naive T cells, Tregs differentiation was not promoted in either of the conditions tested. Therefore, leukemic cells do not promote Tregs differentiation, at least in vitro. The role of TGF-beta during leukemia onset remains therefore elusive.