Abstract

The overall objective of this proposal is to understand the processes which control hematopoietic differentiation at the molecular level. The following specific aims will be addressed: 1. To develop a more complete understanding of the factors which control globin gene expression by: a.) Evaluating the impact on the expression of the mouse beta globin gene of mutation at sites in the IVS2 region which exhibit specific binding and footprinting for tissue specific binding proteins B1 and B2 b.) Further characterizing and purifying DNA binding proteins B1 and B2 and c.) Extending DNA binding studies to additional sites in the mouse beta globin gene. 2. To extend our initial studies identifying mRNA regions which contribute to mRNA stability in beta globin and c-fos mRNAs by: a.) Developing additional chimeric constructs between human c- fos and beta globin mRNAs to discriminate with greater precision mRNA sequences or structures which contribute to the differences in stability between these mRNA species. b.) Extending the chimeric mRNA approach to additional mRNA species including alpha globin, c-myc and delta globin mRNAs. C.) Identifying an inducible expression system which will allow us to extend the evaluation of mRNA stability to differentiating hematopoietic cells d.) Developing biochemical and genetic methods for identifying cellular mechanisms which respond to signals within mRNA molecules which lead to differences in half life. 3.) To develop somatic cell genetic approaches to hematopoietic differentiation by: a. Applying gene transfer procedures to determine the significance of changes in expression levels of specific polypeptides in the control of the differentiation program. b. Developing the use of retroviral vectors for insertional mutagenesis in the MEL cell system c. Developing multidrug resistance gene system for use as a selection system for bone marrow progenitor cells and pluripotent stem cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37CA017575-19
Application #
3481768
Study Section
Special Emphasis Panel (NSS)
Project Start
1978-05-01
Project End
1996-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
19
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139

  Publications

Davis, B M; McCurrach, M E; Taneja, K L et al. (1997) Expansion of a CUG trinucleotide repeat in the 3' untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A 94:7388-93
Sobulo, O M; Borrow, J; Tomek, R et al. (1997) MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci U S A 94:8732-7
Flores, J F; Walker, G J; Glendening, J M et al. (1996) Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma. Cancer Res 56:5023-32
Aburatani, H; Stanton Jr, V P; Housman, D E (1996) High-resolution physical mapping by combined Alu-hybridization/PCR screening: construction of a yeast artificial chromosome map covering 31 centimorgans in 3p21-p14. Proc Natl Acad Sci U S A 93:4474-9
Borrow, J; Shearman, A M; Stanton Jr, V P et al. (1996) The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 12:159-67
Coleman, A; Fountain, J W; Nobori, T et al. (1994) Distinct deletions of chromosome 9p associated with melanoma versus glioma, lung cancer, and leukemia. Cancer Res 54:344-8
Lowe, S W; Bodis, S; Bardeesy, N et al. (1994) Apoptosis and the prognostic significance of p53 mutation. Cold Spring Harb Symp Quant Biol 59:419-26
Lowe, S W; Jacks, T; Housman, D E et al. (1994) Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Sci U S A 91:2026-30
Lowe, S W; Bodis, S; McClatchey, A et al. (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266:807-10
Petty, E M; Gibson, L H; Fountain, J W et al. (1993) Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: implications for 9p tumor-suppressor gene(s). Am J Hum Genet 53:96-104

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