David H. Boldt, M.D.

Professor, Department of Medicine

Chief, Division of Hematology

 Research Interests:

One area of research in Dr. Boldt's laboratory has been regulation of gene transcription by iron and hemin. The laboratory has delineated a novel iron-dependent system of transcriptional regulation. At least two eukaryotic genes, protein kinase C-b and tartrate resistant acid phosphatase (TRAP)/uteroferrin are transcriptionally active in the presence of Fe (III) presented as ferric transferrin whereas both are inhibited at the transcriptional level in the presence of exogenous hemin (ferric protoporphyrin IX). Research in this area now encompasses the following aims: (1) to identify, clone, and sequence genes encoding iron and heme dependent transcription regulatory factors; (2) to study and characterize interactions of these factors with DNA elements and with other nuclear proteins; (3) to identify other genes subjedct to transcriptional regulation by iron and/or heme; and (4) to study roles of the iron/heme dependent transcription factors in hematopoietic cell differentiation.

A second area of research in Dr. BoldtÌs laboratory focuses on biological correlates of adult acute lymphoblastic leukemia. His laboratory serves as a reference laboratory for Southwest Oncology Group lymphoblastic leukemia studies and has access to large numbers of adult All samples. Recent results have documented an extremely high incidence of abnormalities in adult All involving genes which are responsible for regulating cell cycling. These genes include the retinoblastoma susceptibility gene (Rb), the p53 gene, and the genes encoding the cyclin dependent kinase inhibitors, p16/p15. Approximately 80% of patients have at least one abnormality of these genes and nearly half have more than one. Although no single gene abnormality correlated with treatment outcome or prognosis, a relationship has been identified between number of gene abnormalities in a given patient and outcome. This observation adds to our understanding of leukemia biology and represents an important lead in the continuing search for useful prognostic factors in adult ALL.

Other work in this laboratory involves the following aspects of adult ALL: (1) expression of the multidrug resistance (MDR) gene and its relationship to prognosis; (2) expression of the bcl-2 gene and apoptosis pathways; (3) genomic expression scanning using microarray technology; (4) significance of minimal residual disease detection by multiparameter flow cytometry or PCR detection of immunoglobulin or T-cell receptor gene rearrangements; and (5) cell sorting experiments in which ALL bone marrow cells will be sorted into early and committed progenitor populations, then studied for clonal for clonal cytogenetic alterations, tumor suppressor gene abnormalities, and ability to initiate leukemia in vivo. Results will increase our understanding of the cellular and molecular basis for leukemogenesis in adult ALL.

Unique Technical and Clinical Research Capabilities/Instrumentation:

Publications:

Reddy, S.V., Hundley, J.E., Windle, J.J., Alcantara, O., Leach, R.J., Boldt, D.H., and Roodman, G.D. Characterization of mouse tartrate-resistant acid phosphatase (TRAP) gene promoter. J. Bone Min. Res., 10:601-606, 1995.

Reddy, S.V., Alcantara, O., Roodman, G.D., and Boldt, D.H.: Inhibition of tartrate resistant acid phosphatase (TRAP) gene expression by hemin. Identification of a hemin responsive inhibitor of transcription. Blood 88:2288-2297, 1996.

Tsai, T., Davalath, S., Rankin, C., Radich, J.P., Head, D., Appelbaum, F.R., and Boldt, D.H.: Tumor suppressor gene alteration in adult acute lymphoblastic leukemia (ALL). Analysis of retinoblastoma (Rb) and p53 gene expression in lymphoblassts of patients with de novo, relapsed, or refractory ALL treated in Southwest Oncology Group studies. Leukemia 10:1901-1910, 1996.

Reddy,SV, Alcantara,O, and Boldt,DH. Analysis of DNA binding proteins associated with hemin-induced transcriptional inhibition. The hemin responsse element binding protein (HREBP) is a heterogeneous complex that includes the Ku protein. Blood 91:1793-1801,1998.

Boldt,DH. New perspectives on iron. An introduction. Amer. J. Med. Sci.318: 207-212, 1999.  

Key Words:

leukemia biology, tumor suppressor genes, gene transcription, iron, hemin