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HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate

Cancer Gene Therapy volume 27, pages 830–833 (2020)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a poor prognosis hematopoietic malignance characterized by abnormal proliferation and differentiation of hematopoietic stem cells (HSCs). Although advances in treatment have greatly improved survival rates in young patients, in the elderly population, ~70% of patients present poor prognosis. A pan-cancer analysis on the TCGA cohort showed that AML has the second higher HUWE1 expression in tumor samples among all cancer types. In addition, pathway enrichment analysis pointed to RAS signaling cascade as one of the most important pathways associated to HUWE1 expression in this particular AML cohort. In silico analysis for biological processes enrichment also revealed that HUWE1 expression is correlated with 13 genes involved in myeloid differentiation. Therefore, to understand the role of HUWE1 in human hematopoietic stem and progenitor cells (HSPC) we constitutively expressed KRASG12V oncogene concomitantly to HUWE1 knockdown in stromal co-cultures. The results showed that, in the context of KRASG12V, HUWE1 significantly reduces cell cumulative growth and changes myeloid differentiation profile of HSPCs. Overall, these observations suggest that HUWE1 might contribute to leukemic cell proliferation and impact myeloid differentiation of human HSCs, thus providing new venues for RAS-driven leukemia targeted therapy approach.

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Fig. 1: Characterization of HUWE1’s role in myeloid differentiation.

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Funding

This work was supported by National Council for Scientific and Technological Development (CNPq) grant 449527/2014-0 and São Paulo Research Foundation (FAPESP) grants no. 2015/10694-5 and 2015/12146-5. This research was co-funded by the Erasmus + programme of the European Union, International Credit Mobility (ICM) 2016-17.

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Authors and Affiliations

  1. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Mariana Tannús Ruckert, Luis Fernando P. Nagano & Vanessa Silva Silveira

  2. Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Mariana Tannús Ruckert, Annet Z. Brouwers-Vos & Jan Jacob Schuringa

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  1. Mariana Tannús Ruckert
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  2. Annet Z. Brouwers-Vos
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Correspondence to Vanessa Silva Silveira.

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Ruckert, M.T., Brouwers-Vos, A.Z., Nagano, L.F.P. et al. HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate. Cancer Gene Ther 27, 830–833 (2020). https://doi.org/10.1038/s41417-020-0198-3

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