Contact Information

Pediatrics


Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
Phone: (301) 295-9714
Fax: (301) 295-3898
Email: yang.du@usuhs.edu

Pubmed listing

Yang Du, Ph.D.

Assistant Professor

Molecular mechanisms of leukemia development

Growing evidence in the leukemia field supports the cancer stem cell model that leukemia is comprised of a heterogeneous population and only a fraction of the leukemic cells, known as leukemic stem cells (LSCs), are capable of sustaining and regenerating the disease. These immortalized LSCs possess unlimited self-renewal capability and can also differentiate spontaneously into more mature non-leukemic progenies that make up the bulk of the malignancy. LSCs can be derived from hematopoietic stem cells (HSCs) that normally have extensive self-renewal capability or from more mature progenitors that acquire such self-renewal potential through mutations. The clinical implication of this model is that LSCs have to be eliminated in order to eradicate leukemias. Since the hallmark of LSCs is their unlimited self-renewal capability, inhibition of LSC self-renewal represents a promising new strategy for treating leukemias. However, the molecular mechanism(s) controlling LSC self-renewal is poorly understood.

We have recently identified a set of candidate genes for regulating LSC self-renewal in myeloid leukemias in a retroviral insertional mutagenesis screen. Ectopic expression of these genes is able to confer unlimited self-renewal capability to murine myeloid progenitor cells in culture. One major focus in the lab is to confirm these genes as LSC self-renewal regulators by testing effects of their expression on the self-renewal potential and the transformation of normal murine myeloid progenitors in vivo. In order to understand the mechanisms that they regulate LSC self-renewal, expression profiling will be used to identify their downstream targets. Since extensive self-renewal capability is shared between LSCs and normal HSCs, genes identified in our screen may also play important roles in the self-renewal of normal HSCs. Therefore, we are also taking a genetic approach to investigate this possibility by generating hematopoietic specific knockout mouse models for these candidates. Because our insertional mutagenesis screen makes use of retroviral vectors capable of infecting many different cell types, another area of resarch in the lab is to apply the same screening strategy outside of hematopoietic system to identify self-renewal regulators for other cancer stem cell types.

Selected publications:

Oakley K, Han Y, Vishwakarma BA, Chu S, Bhatia R, Gudmundsson K, Keller J, Chen X, Vasko, Jenkins NA, Copeland NG, Du Y. Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10. (2012) Blood 119(25):6099-108.

Aue G, Du Y, Cleveland SM, Smith SB, Davé UP, Liu D, Metais JY, Jenkins NA, Copeland NG, Dunbar CE. Sox4 cooperates with Pu.1 haploinsufficiency in murine myeloid leukemia. (2011) Blood 118:4674-81.

Bosticardo M, Ghosh A, Du Y, Jenkins NA, Copeland NG, Candotti F. Self-inactivating retroviral vector-mediated gene transfer induces oncogene activation and immortalization of primary murine bone marrow cells. (2009) Molecular Therapy. 17(11): 1910-1918.

Jiang X, Tian F, Du Y, Copeland NG, Jenkins NA, Tessarollo L, Wu X, Pan H, Hu XZ, Xu K, Kenney H, Egan SE, Turley H, Harris AL, Marini AM, Lipsky RH. BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. (2008) Journal of Neuroscience. 28:1118-1130.

Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. (2006) Nature Medicine. 12:401-409.

Du Y, Jenkins NA, Copeland NG. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. (2005) Blood. 106: 3932-3939.

Du Y, Spence SE, Jenkins NA, Copeland NG. Cooperating cancer gene identification via oncogenic retrovirus-induced insertional mutagenesis. (2005) Blood. 106: 2498-2505.

Nalbant D, Youn H, Nalbant SI, Sharma S, Cobos E, Beale EG, Du Y, Williams SC. FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells. (2005) BMC Genomics 6: 11.

Du Y, Campbell JL, Nalbant D, Youn H, Bass AC, Cobos E, Tsai S, Keller JR, Williams SC. Mapping gene expression patterns during myeloid differentiation using the EML hematopoietic progenitor cell line. (2002) Experimental Hematology 30: 649-58.

Williams SC, Du Y, Nalbant D, Campbell JL. Novel roles for aldo keto reductases in myeloid differentiation and disease. (2000) Recent Research Developments in Molecular and Cellular Biology 1: 19-30.

Du Y, Tsai S, Keller JR, and Williams SC. Identification of an interleukin-3-regulated aldo-keto reductase gene in myeloid cells that may function in autocrine regulation of myelopoiesis. (2000) Journal of Biological Chemistry 275: 6724-6732.

Angerer ND, Du Y, Nalbant D, and Williams SC. A short conserved motif is required for repressor domain function in the myeloid-specific transcription factor CCAAT/enhancer-binding protein ?. (1999) Journal of Biological Chemistry 274: 4147-4154.

Williams SC, Du Y, Schwartz RC, Weiler SR, Ortiz M, Keller JR, and Johnson PF. C/EBP? is a myeloid-specific activator of cytokine, chemokine, and macrophage-colony-stimulating factor receptor genes. (1998) Journal of Biological Chemistry 273: 13493-13501.

Arkane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, and Strauss JF. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. (1997) Journal of Biological Chemistry 272: 32656-32662.