Positions
- Professor
-
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
- Member
-
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- Faculty Member
-
Development, Disease Models, & Therapeutics Graduate Program
Baylor College of Medicine
- Faculty Member
-
Cancer & Cell Biology Graduate Program
Baylor College of Medicine
- Scholar of the Leukemia and Lymphoma Society
-
Baylor College of Medicine
- CPRIT Scholar in Cancer Research
-
Baylor College of Medicine
Addresses
- One Baylor Plaza (Lab)
-
R713
Houston, TX 77030
United States
Professional Interests
- Normal and malignant stem cells in the blood system
Professional Statement
Hematopoietic stem cells (HSCs) are immature progenitor cells that are responsible for replenishing blood cells that are lost during homeostasis and become activated upon inflammation or injury to promote regeneration. HSCs are multipotent and have the full developmental potential to differentiate into all blood cells types and persist throughout life through a cell division mechanism called self-renewal. Differentiation and self-renewal often go awry in blood cancer, or leukemia, to enable unlimited proliferation of malignant blood cells.The focus of our lab is to study the molecular and cellular mechanisms that regulate self-renewal and differentiation in HSCs and leukemia. We use mouse genetics, genome-editing tools and epigenome profiling to understand how physiological changes and stress conditions stimulate HSCs. We recently developed a lineage-tracing mouse model to trace the fate of HSCs and to study their behavior in vivo. This model is being used to investigate how HSCs respond to hematopoietic insults and the mechanisms by which they regenerate the blood system after stress. We also study how mechanisms that regulate HSCs go awry to cause leukemia. Our recent study indicates that leukemia cells rely on particular metabolic and epigenetic master regulators to support their unlimited proliferative capacity and to block differentiation. Our ongoing studies aim to identify and characterize novel metabolic processes that are essential for leukemia progression that can be targeted for intervention. By studying differentiation and self-renewal mechanisms in normal stem cells and cancer cells, we seek to identify key differences that could be targeted to promote regeneration by normal stem cells and suppress cancer by disabling the aberrant stem cell mechanisms.
Websites
Selected Publications
- Jiang Y, Hu T, Wang T, Shi X, Kitano A, Eagle K, Hoegenauer KA, Konopleva MY, Lin CY, Young NL, Nakada D "AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia.." Blood. 2019;134:2183-2194.
- Hu T, Morita K, Hill MC, Jiang Y, Kitano A, Saito Y, Wang F, Mao X, Hoegenauer KA, Morishita K, Martin JF, Futreal PA, Takahashi K, Nakada D "PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia- initiating cells.." Blood. 2019;134:614-625.
- 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.
- Hu T, Kitano A, Luu V, Dawson B, Hoegenauer KA, Lee BH, Nakada D "Bmi1 Suppresses Adipogenesis in the Hematopoietic Stem Cell Niche." Stem Cell Reports. 2019;13:545-558.
- 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 Feb 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 Oct 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 Jan;505(7484):555-8. Pubmed PMID: 24451543
- 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 Dec 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 Nov 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
- Xiangguo Shi, Yajian Jiang, Ayumi Kitano, Tianyuan Hu, Rebecca L Murdaugh, Yuan Li, Kevin A Hoegenauer, Rui Chen, Koichi Takahashi, Daisuke Nakada "Nuclear NAD + homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells." Sci Adv.. 2021 Jul 21;7(30) Pubmed PMID: 34290089
- Murdaugh RL, Hoegenauer KA, Kitano A, Holt MV, Hill MC, Shi X, Tiessen JF, Chapple R, Hu T, Tseng YJ, Lin A, Martin JF, Young NL, Nakada D "The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells." Stem Cell Reports. 2021 Aug 10;16(8):2014-2028. Pubmed PMID: 34242617
Projects
- 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.
Funding
- Metabolic Regulation in Leukemia-Initiating Cells - #1 R01 CA193235 (07/01/2020 - 06/30/2025) Grant funding from NIH
- Scholar Cancer Prevention Research Institute of Texas (CPRIT)
- THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA - #R01CA255813 NIH
Log In to edit your profile