Email

nakada@bcm.edu

Positions

Associate 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.

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

(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