Laboratory of Chuan-dong Geng, PhD

Glucocorticoids have been widely used to treat various hematopoietic malignancies, especially Acute Lymphoblastic Leukemias (ALLs). The usage of corticosteroids in chemotherapy is based on the discovery that high concentrations of glucocorticoids (GCs) induce programmed cell death (apoptosis) in certain types of lymphoblasts. Interestingly, the killing effects of GCs are limited to these cancer cells, and most other cells are resistant to the apoptotic effect. However, the selective mechanism by which GCs induce apoptosis is still not clear. The incidence of ALL is about 3 in 100,000 children, and, of these, 80%-85% is B-ALL. Currently, the cure rates in ALL are still low at 20%-40%.

Dr. Geng’s specific interest is focused on glucocorticoid induced apoptosis of B-cell acute lymphoblastic Leukemia (B-ALL). The long term goal is to elucidate the mechanism that specifically controls the sensitivity of B-ALLs to GC treatment, as a prerequisite to the development of novel diagnostic and therapeutic protocols. The lytic function of glucocorticoids on leukemic cells depends on its cellular binding protein, the glucocorticoid receptor (GR). It appears that the auto-induction of the cellular GR level above a certain threshold via GC auto-upregulation of hGR gene expression is significant and critical for causing GC induced apoptosis. A number of intracellular factors that affect the auto-upregulation of hGR gene expression during steroid treatment may modulate the therapeutic killing response of ALL leukemic cells. An identification of these intracellular factors is essential for a rational design of treatment regimens for patients.

In human lymphoblasts, GR gene transcription is primarily controlled by 3 promoters (1A, 1B and 1C). The roles of these hGR promoters on auto-upregulation of hGR gene expression in GC sensitive B-ALL were completely unknown. Our pilot studies have shown an alternative usage/regulation of hGR promoters in B-ALL (697 cell), in that promoter 1C is the most important for hGR gene expression and contributes the most to total cellular hGR mRNA transcripts. Even more interestingly, the auto-upregulation of cellular GR expression during GC induced apoptosis in B-ALL solely involves the hormonal response of promoter 1C. The selective use and auto-upregulation of hGR promoter 1C, therefore, is likely to be a critical cellular event controlling GC-induced apoptosis in B-ALL. Clarifying the selective auto-regulatory mechanisms that are involved in hGR promoter 1C regulation in B-ALL is of fundamental importance for defining the role of glucocorticoids in the apoptotic response in these leukemia cells.

Studies performed in our lab have characterized a non-classical glucocorticoid response unit (GRU) in hGR promoter 1A. Depending upon the cell-type specific transcription factors specifically expressed in the lymphoblast cells (c-Myb and PU.1), the activity of promoter 1A is selectively upregulated in GC sensitive CEM-C7 cells and downregulated in GC resistant cells (IM-9) through a “molecular switch” mechanism during GC treatment (Geng, C.-D and Vedeckis, W.V, 2004 & 2005). Our current studies have shown that c-Myb and GR binding sequences are conserved in the promoter DNA sequences mediating the hormonal response of promoter 1C, which controls the hormonal response of this promoter in lymphoblastic cells (Figure). Their functions in the auto-regulatory response of hGR promoter 1C, and the B-ALL specific molecular mechanism involved during GC induced apoptosis, are under intensive study. These studies will be of value in the diagnosis (hormone-sensitive or –resistant) and treatment (what targets on the hGR 1C promoter could be exploited to increase hormone-sensitivity?) of B-cell acute lymphoblastic leukemia in humans.

Recent Publications

Geng, C.-D. and Vedeckis W.V. C-Myb and members of the c-Ets family of transcription factors act as molecular switches to mediate opposite steroid regulation of the human glucocorticoid receptor 1A promoter. J. Biol. Chem. 280: 43264-43271 (2005)

Geng, C.-D., Pedersen, K.B., Nunez, B.S. and Vedeckis, W.V. Human glucocorticoid receptor alpha transcript splice variants with exon 2 deletions: evidence for tissue- and cell type-specific functions. Biochemistry, 44: 7395-405 (2005)

Nunez, B.S., Geng, C.-D., Pedersen, K.B., Millro-Macklin, C.D. and Vedeckis, W.V. Interaction between the interferon signaling pathway and the human glucocorticoid receptor gene 1A promoter. Endocrinology, 146: 1449-1457 (2005)

Garg, R., Geng, C.-D., Miller, J.L., Callens, S., Tang, X., Appel, B. and Xu, B. Molecular cloning and characterization of the catalytic domain of zebrafish homologue of the ataxia-telangiectasia mutated gene. Mol. Cancer Res., 2: 348-353 (2004)

Pedersen, K.B., Geng, C.-D. and Vedeckis, W.V. Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line. Biochemistry, 43:10851-10858 (2004)

Breslin MB, Geng, C.-D. Vedeckis WV. Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. Mol Endocrinol.Aug;15(8):1381-95 (2001)

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