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Title page for ETD etd-03302010-112639


Type of Document Dissertation
Author Dey, Soumyadeep
Author's Email Address soumyadeep.dey@vanderbilt.edu
URN etd-03302010-112639
Title Role of the TAL1/SCL transcription factor in differentiation of bone marrow monocyte-macrophage precursors
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Utpal P. Dave Committee Chair
MacRae F. Linton Committee Member
Scott W. Hiebert Committee Member
Stephen J. Brandt Committee Member
Keywords
  • TRANSCRIPTION FACTOR
  • MONOCYTE-MACROPHAGE
  • HEMATOPOIESIS
  • TAL1
  • CELL CYCLE
  • GENE REGULATION
Date of Defense 2010-03-26
Availability unrestricted
Abstract
TAL1/SCL encodes a basic helix-loop-helix transcription factor and was first identified through its involvement in a chromosomal translocation in T-cell acute lymphoblastic leukemia. The mouse Tal1 cDNA was cloned from a bone marrow (BM) macrophage cDNA library and although Tal1 has critical roles in other hematopoietic lineages, its function in monocyte-macrophage (MM) differentiation has not been studied.

Using an ex vivo system of MM differentiation we detected Tal1 expression at all stages of differentiation including activated macrophages. Over-expression of Tal1 in MM precursor cells increased differentiation and proliferation and activated immune response pathways. Gene knockout studies identified severe cell cycle and proliferative defects in Tal1-null cells but had minimal effects on cell survival and only modestly increased terminal differentiation. In conjunction with the cell cycle defect in Tal1-null cells, steady state levels of p16(Ink4a) mRNA were increased and Gata2 mRNA decreased. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated association of Tal1 and E47, one of its E protein DNA-binding partners, with an E box-GATA element in a Gata2 enhancer and with three E boxes upstream of p16(Ink4a) at early stages of differentiation. But this association became low to non-existent in more mature cells. ChIP analysis in M1 myelo-monocytic leukemia cells detected Tal1 and E2A association in untreated cells and interleukin-6 (IL-6)-induced differentiation lowered Tal1 association only. In contrast, E2A occupancy in p16(Ink4a) sites was detected in both treated and untreated cells, consistent with relief of Tal1-directed repression of p16(Ink4a) in M1 cells upon differentiation. In summary, these studies have uncovered a critical role for Tal1 in cell cycle regulation during monocytopoiesis and suggest that TAL1 repression of p16(Ink4a) transcription and activation of Gata2 likely contributes. Additionally, wild-type Tal1, but not a DNA binding-defective mutant, rescued the proliferative defect in Tal1-null cells that underscores its requirement for DNA binding. Finally, the results in Tal1-over-expressing MM precursors may be relevant to the action of TAL1 in T-lymphoid and, in particular, myeloid leukemias.

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