Joseph Krambs
Program: Molecular Genetics and Genomics
Current advisor: Daniel C. Link, MD
Undergraduate university: Middle Tennessee State University
Research summary
As a graduate student, my initial studies in the laboratory of Dr. Daniel C. Link focused on the hematopoietic bone marrow niche and the contribution stromal cells have on hematopoiesis. Specifically, I have studied the role of SMAD4, a downstream mediator of the TGF-β superfamily signaling, in bone marrow stromal cells in establishing and maintaining the bone marrow hematopoietic stem cell (HSC) niche. We developed a mouse model where SMAD4 is abrogated specifically in mesenchymal stromal cells. We show that the post-natal loss of SMAD4 results in minimal perturbations in basal and stress hematopoiesis, suggesting that TGF-β family signaling is largely dispensable for the maintenance of hematopoietic niches in the bone marrow.
My work as a graduate student has also contributed to our understanding of the dynamic relationship between commensal flora and hematopoiesis. Specifically, we collaborated with Laura G. Schuettpelz to address whether the microbiome assists in establishing myeloid potential in early development and how myeloid potential is maintained with age. We showed, through functional and phenotyping assays, that the commensal flora influences the maintenance of B cell lymphopoiesis with age. We also showed that the commensal flora directs myeloid output in early life through hematopoietic stem cell reprogramming.
My thesis work focused on the impact of nucleolar stress on T cell acute lymphoblastic leukemia (T-ALL) transformation. In brief, our data provide support for a novel model of T-ALL leukemogenesis in which CDKN2A loss is an early event that provides a fitness advantage under conditions of replication stress that leads to an expanded pool of CDKN2A deficient hematopoietic stem cells (HSC) and common lymphoid progenitors. Loss of CDKN2A provides a permissive cellular environment for activating NOTCH mutations by attenuating nucleolar stress, and our data suggest that targeting the nucleolar stress pathway or ribosome biogenesis may have therapeutic activity in T-ALL.
I have also contributed to five other studies characterizing hematopoietic niches in the bone marrow, involving myeloproliferative neoplasms and myelofibrosis, bone marrow resident dendritic cells effects on HSC trafficking and function, bone marrow mesenchymal stromal cell lineage specification, and the effects of radiation on hematopoiesis.
Graduate publications
Yao JC, Oetjen KA, Wang T, Xu H, Abou-Ezzi G, Krambs JR, Uttarwar S, Duncavage EJ, Link DC. 2022 TGF-β signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche. J Clin Invest, 132(11):e154092.
Li S, Yao JC, Oetjen KA, Krambs JR, Xia J, Zhang J, Schmidt AP, Helton NM, Fulton RS, Heath SE, Turnbull IR, Mbalaviele G, Ley TJ, Walter MJ, Link DC. 2022 IL-1b expression in bone marrow dendritic cells is induced by TLR2 agonists and regulates HSC function. Blood, 140(14):1607-20.
Krambs JR, Monlish DA, Gao F, Schuettpelz LG, Link D. 2021 Microbiota Signals Suppress B Lymphopoiesis With Aging in Mice. Front Immunol, 12():767267.
Krambs JR, Abou Ezzi G, Yao JC, Link DC. 2020 Canonical signaling by TGF family members in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions. PLoS ONE, 15(5)::e0233751.
Kapoor V, Collins A, Griffith K, Ghosh S, Wong N, Wang X, Challen GA, Krambs J, Link D, Hallahan DE, Thotala D. 2020 Radiation induces iatrogenic immunosuppression by indirectly affecting hematopoiesis in bone marrow. Oncotarget, 11(19):1681-90.
Abou-Ezzi G, Supakorndej T, Zhang J, Anthony B, Krambs J, Celik H, Karpova D, Craft CS, Link DC. 2019 TGF-β Signaling Plays an Essential Role in the Lineage Specification of Mesenchymal Stem/Progenitor Cells in Fetal Bone Marrow. Stem Cell Reports, 13(1):48-60.
Zhang J, Supakorndej T, Krambs JR, Rao M, Abou-Ezzi G, Ye RY, Li S, Trinkaus K, Link DC. 2019 Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking. J Clin Invest, 129(7):2920-31.