Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development

Abstract

Abnormal activation of SETBP1 through overexpression or missense mutations is highly recurrent in various myeloid malignancies; however, it is unclear whether such activation alone is able to induce leukemia development. Here we show that Setbp1 overexpression in mouse bone marrow progenitors through retroviral transduction is capable of initiating leukemia development in irradiated recipient mice. Before leukemic transformation, Setbp1 overexpression significantly enhances the self-renewal of hematopoietic stem cells (HSCs) and expands granulocyte macrophage progenitors (GMPs). Interestingly, Setbp1 overexpression also causes transcriptional repression of critical hematopoiesis regulator gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediated recruitment of a nucleosome remodeling deacetylase (NuRD) complex to Runx1 promoters and can be reversed by treatment with histone deacetylase (HDAC) inhibitors Entinostat and Vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1 activation-induced leukemia cells in vitro, and significantly extended the survival of mice transplanted with such leukemias, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation.

Somatic SETBP1 mutations in myeloid neoplasms

“…Moreover, by comparison between the same amount of wild-type and mutant SETBP1 proteins, more proliferative potential was observed in the mutant experiments [30]. Mutated proteins also bind more efficiently to DNA at promotor sites of target genes [68,69]. Altogether, SETBP1 mutations were supposed to have both quantitatively and qualitatively activating effects on SETBP1 functions.…”

“…Another SETBP1-mediated oncogenic potential is induced by down-regulation of tumor suppressor RUNX1, whose expression is attenuated through activation of SETBP1 binding more efficiently to promotor sites of RUNX1 (Fig. 8) [68]. An additional target of activated SETBP1 is a well-known oncogene MYB.…”

Genomics of chronic neutrophilic leukemia

“…In this model, SETBP1 overexpression decreases expression of Runx1, an important hematopoietic transcription factor. 46 This repression of Runx1 expression at the messenger RNA level is mediated by recruitment of the nucleosome 46 Negative regulation of Runx1, an important myeloid transcriptional regulation that is often mutated or dysregulated in leukemia, by SETBP1 provides further rationale for the importance of SETBP1 mutations in these myeloid leukemias (Figure 2). After their initial discovery in aCML, SETBP1 mutations were also found in a variety of myeloid malignancies, including secondary AML, CMML, juvenile myelomonocytic leukemia, and MDS.…”

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

“…Conditional in‐activation of Mi‐2β of the NuRD complex caused erythroid leukemia in mice (15). NuRD‐mediated Runx1 repression has been implicated in Setbp1 ‐induced murine myeloid leukemia development (16). In lymphoid cells, Mi‐2β activity is regulated by Ikaros, and release of NuRD in Ikaros‐deficient cells results in lymphoid leukemia (14).…”