A recent study led by Prof. WANG Lan’s group from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences revealed the role and mechanism of SETD2 in Myelodysplastic Syndromes (MDS)-associated leukemogenesis, providing therapeutic targets for treatment of MDS. This study was published online in Blood. 

MDS is one of the most common myeloid malignancies characterized by bone marrow dysplasia, inefficient hematopoiesis, cytopenia and a risk of progression to acute myeloid leukemia (AML). SETD2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. A lot of SETD2 mutations have been found in chronic lymphocytic leukemia, MLL-NRIP3 and MLL-AF9-driven acute leukemia. However, the role of SETD2 in MDS remains unclear.

In this study, the researchers found that low expression of SETD2 correlated with shortened survival in MDS patients. Loss of Setd2 enhanced the ability of NHD13⁺ hematopoietic stem progenitor cells (HSPCs) to self-renew, with the impairment in differentiation/cell death and the increase in the symmetric self-renewal division in vivo. Meanwhile, they found that early progression of MDS to AML in the Setd2-deleted NHD13 mice also associated with abnormal erythroid differentiation and reduced cell death.

Furthermore, the researchers found that Setd2 deficiency upregulated hematopoietic stem cell (HSC) signaling and downregulated the myeloid cell differentiation pathway in the NHD13⁺ HSPCs. RNA-seq and ChIP-seq analysis indicated that S100a9, S100 calcium binding protein A9, was a target gene of Setd2, and the addition of recombinant S100a9 protein weakened the effect of Setd2 deficiency on the NHD13⁺ HSPCs. In contrast, downregulation of S100a9 led to the decreases of its downstream targets, including and Jnk, which influence the self-renewal and differentiation of HSPCs. 

This study revealed, for the first time, that Setd2 acts as an important tumor suppressor in the transformation of NHD13-driven MDS to AML, providing therapeutic targets for treatment of MDS in clinical. 

Setd2 plays an important role in the transformation of NHD13 driven MDS to AML. (Image by Prof. WANG Lan's team)