The long term objective of the research program is to gain a better understanding of the molecular-genetic controls of myelopoiesis and leukemogenesis. An experimental approach to dissect the regulation of differentiation and how differentiation blocks can arise is to genetically manipulate myeloid cells, and to analyze these cells at the cellular, molecular and genetic level. It has been shown that, in addition to constitutive c-myc causing Interleukin-6 (IL-6) treated M1myc cells to arrest at an intermediate stage of differentation, a portion of the IL-6 treated proliferating population of cells undergoes apoptotic cell death. Similar observations were made for the nonleukemic 32D cell line and normal myeloid cells from bone marrow (BM). It is hypothesized that the effects of c-myc on hematopoietic development are mediated via c-myc target genes and genes induced by differentiation factors. The c-myc target gene cdc25A appears to mediate some effects of c-myc on differentiation, and the genes Gadd45, MyD116 and CR6, induced by myeloid differentiation factors, participate in the apoptotic response associated with the block in differentiation. This proposal intends to extend these novel findings, to decipher how these gene products participate in the myc-mediated effects on myeloid development, and to identify other players. Since c-myc is a member of a transcription factor network which regulates c-myc target genes, to understand how c-myc carries out its functions it is necessary to understand this network of interacting factors. The proposed studies will employ the M1 and 32D cell lines, as well as myeloid cells from BM.
The specific aims of this proposal are:
Aim I : Molecular-Genetic Dissection of c-myc-mediated block in differentiation and growth arrest: A role for the c-myc target gene cdc25A and other target genes.
Aim II : Molecular-genetic Dissection of the Apoptotic Response Associated with the Myc- Mediated Block in Terminal Differentiation: A Role for MyD and Gadd Genes.
Aim III : To ascertain the role of the network of c- myc interacting factors in regulating differentiation, growth arrest and apoptosis. These studies should reveal how perturbing c-myc, and, therefore, normal cell cycle controls, can block differentiation, alter cell survival, and promote leukemogenesis. These investigations should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukemias, ultimately aiding in diagnosis, prognosis and eventual therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Schools of Medicine
United States
Zip Code
Maifrede, Silvia; Magimaidas, Andrew; Sha, Xiaojin et al. (2017) Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia. Oncotarget 8:69281-69294
Salerno, Dominic M; Tront, Jennifer S; Hoffman, Barbara et al. (2012) Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling. J Cell Physiol 227:3613-20
Liebermann, Dan A; Tront, Jennifer S; Sha, Xiogen et al. (2011) Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncog 16:129-40
Cretu, Alexandra; Sha, Xiaojin; Tront, Jennifer et al. (2009) Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer Ther 7:268-276
Liebermann, Dan A; Hoffman, Barbara (2009) Good and bad IRF-1: role in tumor suppression versus autoimmune disease. Leuk Res 33:1301-2
Zumbrun, Steven D; Hoffman, Barbara; Liebermann, Dan A (2009) Distinct mechanisms are utilized to induce stress sensor gadd45b by different stress stimuli. J Cell Biochem 108:1220-31
Gibbs, J D; Liebermann, D A; Hoffman, B (2008) Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia. Oncogene 27:98-106
D'Angelo, Santo; Liebermann, Dan; Hoffman, Barbara (2008) The c-myc apoptotic response is not intrinsic to blocking terminal myeloid differentiation. J Cell Physiol 216:120-7
Gibbs, J D; Liebermann, D A; Hoffman, B (2008) Leukemia suppressor function of Egr-1 is dependent on transforming oncogene. Leukemia 22:1909-16
Hoffman, Barbara; Liebermann, Dan A (2007) Role of gadd45 in myeloid cells in response to hematopoietic stress. Blood Cells Mol Dis 39:344-7

Showing the most recent 10 out of 19 publications