Abstract
SETBP1 missense mutations have been frequently identified in multiple myeloid neoplasms; however, their oncogenic potential remains unclear. Here we show that expression of Setbp1 mutants carrying two such mutations in mouse bone marrow progenitors efficiently induced development of acute myeloid leukemias (AMLs) in irradiated recipient mice with significantly shorter latencies and greater penetrance than expression of wild-type Setbp1, suggesting that these mutations are highly oncogenic. The increased oncogenicity of Setbp1 missense mutants could be due in part to their capability to drive significantly higher target gene transcription. We further identify Myb as a critical mediator of Setbp1-induced self-renewal as its knockdown caused efficient differentiation of myeloid progenitors immortalized by wild-type Setbp1 and Setbp1 missense mutants. Interestingly, Myb is also a direct transcriptional target of Setbp1 and Setbp1 missense mutants as they directly bind to the Myb locus in immortalized cells and dramatically activate a critical enhancer/promoter region of Myb in luciferase reporter assays. Furthermore, Myb knockdown in Setbp1 and Setbp1 missense mutations-induced AML cells also efficiently induced their differentiation in culture and significantly prolonged the survival of their secondary recipient mice, suggesting that targeting MYB pathway could be a promising strategy for treating human myeloid neoplasms with SETBP1 activation.
Highlights
Missense mutations of SETBP1 are highly recurrent in multiple myeloid neoplasms, including atypical chronic myeloid leukemia [1], chronic myelomonocytic leukemia (CMML) [2], secondary acute myeloid leukemia [2], juvenile myelomonocytic leukemia (JMML) [3], and chronic neutrophilic leukemia (CNL) [4, 5], suggesting that they may play an important role in the development of these malignancies
These results suggest that SETBP1 missense mutations are highly oncogenic, with significantly higher transforming potential than wild-type SETBP1 in inducing acute myeloid leukemias (AMLs) development
We showed previously that expression of these mutations in committed myeloid progenitors efficiently induced their immortalization in culture; these cells failed to induce leukemia development when transplanted into lethally-irradiated recipient mice
Summary
Missense mutations of SETBP1 are highly recurrent in multiple myeloid neoplasms, including atypical chronic myeloid leukemia [1], chronic myelomonocytic leukemia (CMML) [2], secondary acute myeloid leukemia (sAML) [2], juvenile myelomonocytic leukemia (JMML) [3], and chronic neutrophilic leukemia (CNL) [4, 5], suggesting that they may play an important role in the development of these malignancies. The association of SETBP1 missense mutations with poor prognosis in many of these diseases further suggests that improved therapeutic strategies for patients with such mutations are critically needed. It remains unclear, how SETBP1 mutations may contribute to the development and progression of these myeloid neoplasms. It has been suggested that these mutations may increase stability of SETBP1 protein [1] Consistent with this idea, oncogenic activities previously identified with overexpression of wild-type SETBP1 have been found to associate with SETBP1 mutations: inhibition of tumor suppressor protein phosphatase type 2A (PP2A) [6], and transcriptional activation of Hoxa and Hoxa10 [7]. The oncogenic potential of SETBP1 missense mutations in vivo remains to be thoroughly examined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
