RUNX1 is a transcription factor required for the formation of the hematopoietic stem cell (HSC) and for its further maturation. RUNX1 is commonly mutated or involved in chromosomal translocations associated with AML or ALL. Dr. Friedman''s laboratory is investigating the mechanisms that allow RUNX1 to regulate normal hematopoietic stem cells and myeloid differentiation and to stimulate cell cycle progression. He ultimately envisions developing means to manipulate RUNX1 to assist formation and expansion of HSC from embryonic stem cells and to assist formation of autologous neutrophils to benefit patients with neutropenia. In addition, Dr. Friedman is investigating how mutations of RUNX1 or its partner CBFb contribute to acute leukemia, focusing on CBFb-SMMHC, a fusion oncoprotein expressed from the inv(16) chromosome in a subset of AML patients. Ultimately, he would like to identify small molecules that target CBFb-SMMHC to assist in the therapy of AML.
C/EBPa is a transcription factor required for formation of normal neutrophils and monocytes. C/EBPa is also commonly mutated in blasts derived from patients with AML. Dr. Friedman''s laboratory is investigating how C/EBPa cooperates with other proteins, including cytokines such as G-CSF or M-CSF, to control normal myeloid development. In addition, he is investigating how mutant forms of C/EBPa contribute to AML, in particular focusing on how interaction between C/EBPa and another transcription factor, NF-kB, inhibits apoptosis. By mapping the amino acids through which these proteins interact, Dr. Friedman hopes to ultimately design small molecules that prevent their interaction to induce leukemic cell death and contribute to the therapy of AML. As C/EBPs and NF-kB are also expressed also in other malignancies and in inflammatory cells which contribute to cancer formation and progression, such a small molecule might in addition have broader utility as a novel therapeutic.
Dr. Friedman investigates mechanisms through which normal proteins control the formation of bone marrow stem cells and how these stem cells then develop into neutrophils and monocytes. He is also studying how normal bone marrow cells become transformed into acute myeloid leukemia (AML). In conducting these studies he focuses on two proteins, RUNX1 and C/EBPa, which regulate normal bone marrow development but are also commonly mutated in AML. Dr. Friedman is attempting to build on his basic research to develop useful clinical applications. In particular, he is pursuing small molecules that interfere with the action of leukemic RUNX1 or C/EBPa proteins as potential novel therapies for AML, and he is investigating means to expand normal blood stem cells to benefit patients with marrow failure or those many patients receiving chemotherapy who would benefit from blood product support to avoid anemia, bleeding, and infections.
Nguyen-Khac, F.; Della Valle, V.; Lopez, R.G.; Ravet, E.; Mauchauffe, M.; Friedman, A.D.; Huang, L.E.; Fichelson, S.; Ghysdael, J.; Bernard, O.A. Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation. Oncogene. 2006 Aug 10;25(35):4840-4847.
Suh, H.C.; Gooya, J.; Renn, K.; Friedman, A.D.; Johnson, P.F.; Keller, J.R. C/EBPalpha determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood. 2006 Jun 1;107(11):4308-4316.
Wang, D.; D'Costa, J.; Civin, C.I.; Friedman, A.D. C/EBPalpha directs monocytic commitment of primary myeloid progenitors. Blood. 2006 Aug 15;108(4):1223-1229.
Yu, X.; Alder, J.K.; Chun, J.H.; Friedman, A.D.; Heimfeld, S.; Cheng, L.; Civin, C.I. HES1 inhibits cycling of hematopoietic progenitor cells via DNA binding. Stem Cells. 2006 Apr;24(4):876-888.
Zhang, L.; D'Costa, J.; Kummalue, T.; Civin, C.I.; Friedman, A.D. Identification of a region on the outer surface of the CBFbeta-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization. Oncogene. 2006 Nov 23;25(55):7289-7296.
Friedman, A.D. C/EBPalpha induces PU.1 and interacts with AP-1 and NF-kappaB to regulate myeloid development. Blood cells, molecules & diseases. 2007 Nov-Dec;39(3):340-343.
Friedman, A.D. Normal and malignant hematopoiesis. Oncogene. 2007 Oct 15;26(47):6686.
Friedman, A.D. Transcriptional control of granulocyte and monocyte development. Oncogene. 2007 Oct 15;26(47):6816-6828.
Yeamans, C.; Wang, D.; Paz-Priel, I.; Torbett, B.E.; Tenen, D.G.; Friedman, A.D. C/EBPalpha binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment. Blood. 2007 Nov 1;110(9):3136-3142.
Cai, D.H.; Wang, D.; Keefer, J.; Yeamans, C.; Hensley, K.; Friedman, A.D. C/EBP alpha:AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBP alpha homodimers or AP-1. Oncogene. 2008 Apr 24;27(19):2772-2779.
Kuo, D.Z.; Milstone, A.M.; Omokaro, S.O.; Friedman, A.D.; Karanjawala, Z.E.; Borowitz, M.; Joyner, M.L.; Halsey, N.A.; Sibinga, E.M. Epstein-Barr virus-associated central nervous system lymphoproliferative disease in a patient with acquired immunodeficiency syndrome responsive to highly active antiretroviral therapy. Clin Infect Dis. 2008 May 1;46(9):1476-1478.
Zhang, L.; Fried, F.B.; Guo, H.; Friedman, A.D. Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation. Blood. 2008 Feb 1;111(3):1193-1200.
Friedman, A.D. Cell cycle and developmental control of hematopoiesis by Runx1. J Cell Physiol. 2009 Jun;219(3):520-524.
Jack, G.D.; Zhang, L.; Friedman, A.D. M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood. 2009 Sep 3;114(10):2172-2180.
Paz-Priel, I.; Ghosal, A.K.; Kowalski, J.; Friedman, A.D. C/EBPalpha or C/EBPalpha oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-kappaB p50 bound to the bcl-2 and FLIP gene promoters. Leukemia. 2009 Feb;23(2):365-374.
Wang, D.; Paz-Priel, I.; Friedman, A.D. NF-kappa B p50 regulates C/EBP alpha expression and inflammatory cytokine-induced neutrophil production. J Immunol. 2009 May 1;182(9):5757-5762.
Friedman, A.D. Erythroid maturation and proliferation arrest: The GATA-1 connection. Cell Cycle. 2010 Dec 14;9(10):1873-1877.
Guo, H.; Friedman, A.D. Phosphorylation of RUNX1 by cyclin-dependent kinase reduces direct interaction with HDAC1 and HDAC3. J Biol Chem. 2011 Jan 7;286(1):208-215.
D'Costa J., Chaudhuri S., Civin C.I., and Friedman A.D. (2005). CBFb-SMMHC slows proliferation of primary murine and human myeloid progenitors. Leukemia 19:921-9.
Paz-Priel I., Cai D.H., Wang D., Kowalski J., Blackford A., Liu H., Heckman C.A., Gombart A., Koeffler HP, Boxer LM, and Friedman AD. (2005). C/EBPa and C/EBPa myeloid oncoproteins induce bcl-2 via interaction of their basic regions with NF-kB p50. Mol. Cancer Res. 3:585-96.
Wang D., D''Costa J., Civin C.I., and Friedman A.D. (2006). C/EBPa directs monocytic commitment of primary myeloid progenitors. Blood 108:1223-29.
Zhang L., D''Costa J., Kummalue T., Civin C.I., and Friedman A.D. (2006). Identification of a Region on the Outer Surface of the CBFb-SMMHC Myeloid Oncoprotein Assembly Competence Domain Critical for Multimerization. Oncogene 25:7289-96.
Yeamans C., Wang D., Paz-Priel I., Torbett B.E., Tenen D.G., and Friedman A.D. (2007). C/EBPa binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment. Blood 110;3136-42.
Friedman, A. D. (2007). Transcriptional control of granulocyte and monocyte development. Oncogene 26:6816-28. (review).
Zhang L., Fried F.B., Guo H., and Friedman A.D. (2008). Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on three sites increases trans-activation potency and stimulates cell proliferation. Blood 111:1193-1200.
Cai D.H., Wang D., Keefer J., Yeamans C., Hensley K., and Friedman A.D. (2008). C/EBPa:AP-1 leucine zipper heterodimers bind novel DNA element, activate the PU.1 promoter, and direct monocyte lineage commitment more potently Than C/EBPa homodimers or AP-1. Oncogene 27:2772-9.
Paz-Priel I., Ghosal A.K, Kowalski J., and Friedman A.D. (2009). C/EBP? or C/EBP? 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 23:365-74.
Wang D., Paz-Priel I., and Friedman A.D. (2009). NF-kB p50 regulates C/EBPa expression and inflammatory cytokine-induced neutrophil production. J. Immunol. 2009; 182:5757-62.
Friedman A,D. (2009). Cell cycle and development control of hematopoiesis by Runx1. J. Cell. Physiol. 219:520-524. (review).
Jack G.D, Zhang L., Friedman A.D. (2009). 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,114:2172-80.
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.
Hong SH, Skaist AM, Wheelan SJ, Friedman AD. AP-1 protein induction during monopoiesis favors C/EBP:AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription. J. Leuk. Biol., 2011; 90:643-51.
Faraday N, Yanek LR, Yang XP, Mathias R, Herrera-Galeano JE, Suktitipat B, Qayyum R, Johnson AD, Chen MH, Tofler GH, Ruczinski I, Friedman AD, Gylfason A, Thorsteinsdottir U, Bray PF, O'Donnell CJ, Becker DM, Becker LC. Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression. Blood, 2011; 337:3367-75.
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.
Ma O, Hong S, Guo H, Ghiaur G, Friedman AD. Granulopoiesis requires increased C/EBPα compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells. PLoS One. 2014; 9:e95784.
Guo H, Ma O, Friedman AD. The Cebpa +37 kb enhancer directs transgene expression to myeloid progenitors and to long-term hematopoietic stem cells. J. Leuk. Biol. 2014; 96:419-26.