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.
- Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplantDonor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplantBednarski, J. J., Zimmerman, C., Berrien-Elliott, M. M., Foltz, J. A., Becker-Hapak, M., Neal, C. C., Foster, M., Schappe, T., McClain, E., Pence, P. P., Desai, S., Kersting-Schadek, S., Wong, P., Russler-Germain, D. A., Fisk, B., Lie, W. R., Eisele, J., Hyde, S., Bhatt, S. T., Griffith, O. L., & 4 othersGriffith, M., Petti, A. A., Cashen, A. F. & Fehniger, T. A., Mar 17 2022, In: Blood. 139, 11, p. 1670-1683 14 p.Research output: Contribution to journal › Article › peer-review
- Assessing DNA Damage Responses Using B Lymphocyte CulturesJohnston, R., White, L. S. & Bednarski, J. J., 2022, Methods in Molecular Biology. Humana Press Inc., p. 69-80 12 p. (Methods in Molecular Biology; vol. 2444).Research output: Chapter in Book/Report/Conference proceeding › Chapter › peer-review
- Immunological Findings and Clinical Outcomes of Infants With Positive Newborn Screening for Severe Combined Immunodeficiency From a Tertiary Care Center in the U.S.Immunological Findings and Clinical Outcomes of Infants With Positive Newborn Screening for Severe Combined Immunodeficiency From a Tertiary Care Center in the U.S.Mantravadi, V., Bednarski, J. J., Ritter, M. A., Gu, H., Kolicheski, A. L., Horner, C., Cooper, M. A. & Kitcharoensakkul, M., Sep 3 2021, In: Frontiers in immunology. 12, 734096.Research output: Contribution to journal › Article › peer-review
- Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in miceKim, S. P., Srivatsan, S. N., Chavez, M., Shirai, C. L., White, B. S., Ahmed, T., Alberti, M. O., Shao, J., Nunley, R., White, L. S., Bednarski, J., Pehrson, J. R. & Walter, M. J., Aug 31 2021, In: Cell Reports. 36, 9, 109626.Research output: Contribution to journal › Article › peer-review
- A Case of Severe Combined Immunodeficiency Missed by Newborn ScreeningKitcharoensakkul, M., Aluri, J., Elsharkawi, I., Steed, A., Putnam, C. D., Swayampakula, A. K., Cooper, M. A. & Bednarski, J. J., Aug 2021, In: Journal of Clinical Immunology. 41, 6, p. 1352-1355 4 p.Research output: Contribution to journal › Letter › peer-review