Daisuke Nakada, Ph.D.
Daisuke Nakada, Ph.D.
- Associate Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- One Baylor Plaza (Lab)
Houston, TX 77030
- Normal and malignant stem cells in the blood system
- Richard H. Chapple, Yu-Jung Tseng, Tianyuan Hu, Ayumi Kitano, Makiko Takeichi, Kevin A. Hoegenauer and Daisuke Nakada "Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis." Blood Advances. 2018 2 : 1220-1228.
- Shi X, Kitano A, Jiang Y, Luu V, Hoegenauer KA, Nakada D. "Clonal expansion and myeloid leukemia progression modeled by multiplex gene editing of murine hematopoietic progenitor cells.." Exp Hematol.. 2018 May ; : Pubmed PMID: 29751067
- Chapple RH, Hu T, Tseng YJ, Liu L, Kitano A, Luu V, Hoegenauer KA, Iwawaki T, Li Q, Nakada D. "ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response.." eLife. 2018 February 16; : Pubmed PMID: 29451493
- Gundry MC, Brunetti L, Lin A, Mayle AE, Kitano A, Wagner D, Hsu JI, Hoegenauer KA, Rooney CM, Goodell MA, Nakada D. "Highly Efficient Genome Editing of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9.." Cell Reports. 2016 October 25; : Pubmed PMID: 27783956
- Saito Y, Chapple RH, Lin A, Kitano A, Nakada D. "AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.." Cell Stem Cell. 2015 : Pubmed PMID: 26440282
- Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y, Takeichi M, Wendt GR, Morrison SJ "Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy.." Nature. 2014 January ; 505 (7484): 555-8. Pubmed PMID: 24451543
- Magee JA, Ikenoue T, Nakada D, Lee JY, Guan KL, Morrison SJ "Temporal Changes in PTEN and mTORC2 Regulation of Hematopoietic Stem Cell Self-Renewal and Leukemia Suppression.." Cell Stem Cell. 2012 September 7; 11 (3): 415-28. Pubmed PMID: 22958933
- Yamada T, Park CS, Burns A, Nakada D, Lacorazza HD "The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells.." PLoS ONE. 2012 7 (5): e38280. Pubmed PMID: 22693613
- Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, Saltiel AR, Inoki K "Inhibition of AMPK Catabolic Action by GSK3.." Mol. Cell. 2013 May 9; 50 (3): 407-19. Pubmed PMID: 23623684
- Nakada D, Levi BP, Morrison SJ "Integrating physiological regulation with stem cell and tissue homeostasis.." Neuron. 2011 May 26; 70 (4): 703-18. Pubmed PMID: 21609826
- Nakada D, Saunders TL, Morrison SJ "Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells.." Nature. 2010 December 2; 468 (7324): 653-8. Pubmed PMID: 21124450
- Lee JY, Nakada D, Yilmaz OH, Tothova Z, Joseph NM, Lim MS, Gilliland DG, Morrison SJ "mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.." Cell Stem Cell. 2010 November 5; 7 (5): 593-605. Pubmed PMID: 21040901
- He S, Nakada D, Morrison SJ "Mechanisms of stem cell self-renewal.." Annu. Rev. Cell Dev. Biol.. 2009 25 : 377-406. Pubmed PMID: 19575646
- Regulation of hematopoietic stem cells by systemic factors and the microenvironment
- HSCs divide rarely (a feature called quiescence) but become activated and divide frequently upon stress, such as infection or injury, in order to facilitate immune responses or to promote hematopoietic regeneration. We discovered that a female sex hormone estrogen stimulates HSC division, and that estrogen promotes HSC division and red blood cell production during pregnancy (Nakada et al., Nature. 2014). More recently, we discovered that estrogen activates the unfolded protein response (UPR) in HSCs, endowing them with increased capacity to cope with stress and to promote regeneration (Chapple et al., eLife. 2018). We are using a combination of approaches, including transplantation, epigenome profiling, and CRISPR-mediated gene editing, to understand how estrogen stimulates HSCs.
- Metabolism in leukemia stem cells
- Cancer cells often exhibit aberrant metabolic regulation, such as high dependence on glucose or glutamine metabolism. We are interested in identifying metabolic regulations that are important in leukemia cells but are less important in HSCs and normal hematopoietic cells. We identified a metabolic master regulator for cancer cells that is dispensable for normal HSCs, called AMPK (Saito et al., Cell Stem Cell. 2015). AMPK was particularly important for the immature leukemia cells called leukemia stem cells, and inhibiting this pathway rendered leukemia stem cells unfit to reside in the hypoxic bone marrow environment leading to their demise. Our ongoing work has revealed that AMPK has pervasive effects on leukemia stem cells beyond metabolism, such as gene regulation.
- Development of new genetic models of hematological malignancies using the CRISPR/Cas9 system
- Recent advances in genome editing tools, in particular the CRISPR/Cas9 system, has transformed the way in which genetic studies are performed in multiple model systems. However, until recently, performing genome editing in primary HSCs remained challenging. We recently developed a method to directly modify the genomes of both mouse and human HSCs using the CRISPR/Cas9 system (Gundry et al., Cell Reports. 2016). With this method, we were able to delete genes in more than 75% of HSCs to evaluate gene function in primary HSCs. Moreover, we further optimized the method to perform multiplexed genome editing of mouse HSCs and demonstrated that this method can be used to generate novel mouse models of acute myeloid leukemias by combinatorially deleting up to five genes recurrently mutated in human leukemias (Shi et al. In press). We are using this method to create new leukemia models to better understand how mutations cooperate to transform hematopoietic progenitor cells.
- Metabolic Regulation in Leukemia-Initiating Cells - #1 R01 CA193235 (04/01/2015 - 03/31/2020) Grant funding from NIH
- Mesenchymal stromal cells regulate hematopoietic stem cell aging - #R01DK107413 (01/01/2016 - 12/31/2019) NIH
- Scholar Cancer Prevention Research Institute of Texas (CPRIT)
- RP160035 Cancer Prevention Research Institute of Texas
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