Jeffrey J. Bednarski II, M.D., Ph.D.

Assistant Professor

Immunology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-454-6018

  • 8116


  • Understanding the signals that direct early B cell development

Research Abstract:

My research has centered on understanding the signals that direct early B cell development. Specifically, over the last several years, we have focused on understanding how signals induced by DNA damage impact developmental signals in B cells. B cell development occurs through a carefully regulated process that centers on the generation of a mature, non-autoreactive antigen receptor. To produce a mature antigen receptor, B cells must intentionally generate and repair DNA breaks in the antigen receptor genes. The creation of these DNA breaks is highly regulated by cooperative signaling from two surface proteins, the pre-B cell receptor (pre-BCR) and the interleukin-7 receptor. Together these two signals control cell cycle proliferation and arrest, induction of genes required for antigen receptor gene rearrangement, and cell viability. Our previous work has shown that the physiologic DNA breaks themselves activate a DNA damage response (DDR) that coordinates expression of a cell-type specific genetic program, which cooperates with these surface receptors to impact developmental programing. Our recent work has centered on the impact of DDR on pre-BCR signaling in early B cells. Through RNA profiling, we have found that DDR responses induce expression of SPIC, an ETS-family transcription factor with restricted expression in hematopoietic cells. SPIC shares DNA binding homology with PU.1 and SPIB, two transcription factors with essential roles in early B cell development. However, SPIC has a unique transactivation domain and previous work has suggested that it may function to oppose PU.1 and SPIB activities. We have found that expression of SPIC downstream of DDR results in suppression of key signaling molecules, SYK and BLNK, downstream of the pre-BCR resulting in attenuation of its signaling. Consequently, SPIC results in feedback inhibition of antigen receptor gene assembly and in suppression of pre-BCR driven proliferation. SYK and BLNK are essential for B cell maturation but dysregulated expression of these genes is associated with transformation into B cell leukemia. We hypothesize that signals from DNA breaks activate a feedback loop that tunes B cell developmental signals and suppresses oncogenic transformation.

Selected Publications:

Bednarski JJ, Nickless A, Bhattacharya D, Amin RH, Schlissel MS, Sleckman BP. RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation. J. Exp. Med. 2012; 209: 11-17 PMCID: PMC3260864

Bednarski JJ, Sleckman BP. Lymphocyte Development: Integration of DNA Damage Response Signaling. Adv. Immunol. 2012; 116:175-204 PMID: 23063077

Bednarski JJ, Sleckman BP. Integrated Signaling in Developing Lymphocytes: The Role of DNA Damage Responses. Cell Cycle. 2012; 11:4129-34 PMID: 23032308

Steinel NC, Lee BS, Tubbs AT, Bednarski JJ, Schulte E, Yang-lott KS, Schatz DG, Sleckman BP, Bassing CH. The ataxia telangiectasia mutated kinase controls Igk allelic exclusion by inhibitin secondary Vk-to-Jk rearrangements. J. Exp. Med. 2013; 210: 233-9 PMID: 23382544

Koues OI, Kowalewski RA, Chang L-W, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM. Enhancer Sequence Variants and Transcription Factor Deregulation Synergize to Construct Pathogenic Regulatory Circuits in B Cell Lymphoma. Immunity. 2015; 42:186-98 PMCID: PMC4302272

Last Updated: 7/22/2015 2:52:46 PM

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