|Department Affiliations||Departments of Oncology and Pediatrics|
|SOM Address||Room 253 Cancer Research Building I|
Qianfei Wang 1997 – 2002
A fundamental problem in biology is how stem cells develop into multiple, specific lineages. The development of blood cells from hematopoietic stem cells (HSC) is a widely studied system in mouse and man. We are investigating how transcription factors and plasma membrane receptors signals cooperate to allow HSC to develop into myeloid cells (the granulocytic and monocytic white blood cells), how oncogenic forms of myeloid transcription factors contribute to leukemic transformation of HSC, and how hematopoietic regulators might be used to advantage to expand and differentiate stem cells for eventual clinical use.
By investigating genes expressed specifically in early myeloid genes we identified RUNX1 and C/EBPa as key regulators of myeloid differentiation. RUNX1 is an important proto-oncogene, being involved in several translocations associated with acute myeloid and lymphoid leukemias. Point mutations in the RUNX1 and C/EBP genes are also seen in leukemia. We have found that RUNX1 stimulates the cell cycle in hematopoietic cells and is itself activated by cyclin-dpendent kinases. We are currently validating our model for granulopoiesis in which GCSF signals activate Src kinases to activate RUNX1 to directly activate the C/EBPa gene via a conserved +37 kb enhancer and for monopoiesis in which MCSF signals activate ERK to phosphorylate and so inactivate C/EBPa. We believe that C/EBPa leucine zipper dimers direct granulopoiesis while C/EBP:AP-1 heterodimers drive monopoiesis. We are also investigating how oncogenic RUNX1 or C/EBPa variants block these pathways of normal differentiation. We found also that C/EBPa or C/EBPb inhibit apoptosis in cooperation with the p50 subunit of NF-kB, by displacing HDACs to activate NF-kB target genes. We are validating the idea of targeting the C/EBP:p50 interaction to induce cell death and reduce expression of inflammatory mediators in cancer cells, focusing currently on prostate and breast cancer as well as conducting related studies in normal macrophages. Finally we are interesting in manipulating RUNX1, C/EBPa, and external signals in embryonic stem cells and iPSC to induce them to from hematopoietic stem cells or mature granulocytes for clinical application.
- Zhang L, Fried FB, Guo H, and Friedman AD. Cyclin-Dependent Kinase Phosphorylation of RUNX1/AML1 on Three Sites Increases Trans-Activation Potency and Stimulates Cell Proliferation. Blood 2008; 111:1193-1200.
- Cai DH, Wang D, Keefer J, Yeamans C, Hensley K, and Friedman AD. C/EBPa:AP-1 Leucine Zipper Heterodimers Bind Novel DNA Elements, Activate the PU.1 Promoter, and Direct Monocyte Lineage Commitment More Potently Than C/EBP Homodimers or AP-1. Oncogene 2008; 27:2772-2779.
- Paz-Priel I, Ghosal AK, Kowalski J, and Friedman AD. C/EBPa or C/EBPa oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-kB p50 bound to the bcl-2 and FLIP gene promoters. Leukemia 2009; 23:365-374.
- Wang D, Paz-Priel I, and Friedman AD. NF-kB p50 Regulates C/EBPa Expression and Inflammatory Cytokine-Induced Neutrophil Production. J. Immunol. 2009; 182:5757-5762.
- Jack GD, Zhang L, Friedman AD. M-CSF elevates c-Fos and phospho-C/EBPa(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood, 2009; 114:2172-2180.
- Guo H, Friedman AD. Phosphorylation of RUNX1 by cyclin-dependent kinase reduces direct interaction with HDAC1 and HDAC3. J. Biol. Chem., 2011; 286:208-215.
- Paz-Priel I, Houng S, Dooher J, Friedman AD. C/EBPα and C/EBPα oncoproteins regulate nfkb1 and displace histone deacetylases from NF- κB p50 homodimers to induce expression of NF-κB target genes. Blood, 2011; 117:4085-4094.
- Zhang L, Friedman AD. SHP2 tyrosine phosphatase stimulates CEBPA gene expression to mediate cytokine-dependent granulopoiesis. Blood 2011; 118:2266-2274.
- Dooher JE, Paz-Priel I, Houng S, Baldwin, AS Jr, Friedman AD. C/EBPa, C/EBPa oncoproteins, or C/EBPb preferentially bind NF-kB p50 compared with p65 focusing therapeutic targeting on the C/EBP:p50 interaction. Mol. Cancer Res., 2011; 9:1395-1405.
- Guo H, Ma O, Speck NA, Friedman AD. Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood, 2012; 119:4408-18.