Irwin D. Bernstein
M.D., New York University, 1967.
The research in Dr. Bernstein's lab has primarily focused on developmental aspects of hematopoiesis with the specific goal of developing novel therapeutic modalities. In these efforts we have identified maturation linked cell surface antigens and have utilized this information for developing methods for targeted therapy of hematologic malignancies and for isolating and characterizing normal and malignant human hematopoietic stem cells. These studies have led to the development of stem cell transplantation using isolated CD34+ cells and for Notch ligand-induced expansion of repopulating cell numbers currently being tested in a clinical trial of cord blood transplantation. Our studies of malignant hematopoiesis have examined the clonal origin of AML and have suggested that in some patients, the leukemic cells develop from a clone of mature CD33+ progenitors, or that the leukemia involves only occasional less mature CD33- precursor cells that expand in an uncontrolled manner after maturation to a CD33+ CFC. For these patients, we have hypothesized that ablation of CD33+precursors would restore normal hematopoiesis in patients with AML. On this basis, in collaboration with Wyeth-Ayerst, we have developed a conjugate for the selective ablation of CD33+ cells and demonstrated its ability to induce remissions in at least some patients with AML, supporting the notion of the predominantly or completely normal origin of the CD33- precursors. This conjugate has been approved by the FDA and our current studies are evaluating the effects of multi-drug resistance genes and the stem cell origin of AML on the efficacy of this drug.
Current studies of normal hematopoiesis are aimed at determining methods to direct primitive hematopoietic precursors to commit to a particular maturational pathway or to self-renew. The studies focus on the role of Notch signaling in the regulation of cell fate decisions during hematopoietic differentiation. These studies have demonstrated that constitutive Notch1 signaling can enhance self-renewal and immortalization of cytokine-dependent pluripotent hematopoietic stem cells. We have further demonstrated that Notch signaling induced by interaction of hematopoietic precursor cells with exogenous Notch ligand enhances the formation of primitive multipotential precursors and are presently evaluating whether the formation of hematopoietic stem cells is also enhanced. Based on these findings we developed novel methods for enhancing the repopulating capacity of human hematopoietic precursor cells. In studies with cord blood cells, culture with engineered Notch ligand led to a substantial increase in the number of CD34+ cells and in the rate and magnitude of repopulation in immunodeficient mice. In a Phase I clinical trial in patients with hematologic malignancies, we demonstrated that these cells will provide rapid early engraftment, and hypothesize they will decrease the early transplant related morbidity and mortality seen in patients undergoing umbilical cord blood transplantation and may also contribute to improvement in overall survival.
American Cancer Society
Visualizing human ESC-derived hematopoiesis.. Blood. 121(5):717-8.. 2013.
Engineering stem cell expansion.. Cell stem cell. 10(2):113-4.. 2012.
SIRT1 is dispensable for function of hematopoietic stem cells in adult mice.. Blood. 119(8):1856-1860.. 2012.
Activation of Notch Signaling During ex vivo Expansion Maintains Donor Muscle Cell Engraftment.. Stem cells (Dayton, Ohio).. 2012.
Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells.. The Journal of clinical investigation. 121(3):1207-16.. 2011.
Ex vivo expansion of human hematopoietic stem and progenitor cells.. Blood. 117(23):6083-90.. 2011.
Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions.. Blood. 117(17):4449-59.. 2011.
Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 24(5):909-13.. 2010.
Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.. Cell stem cell. 6(3):251-64.. 2010.
Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.. Nature medicine. 16(2):232-6.. 2010.
Combination of HOXB4 and Delta-1 ligand improves expansion of cord blood cells.. Blood. 116(26):5859-66.. 2010.
E47 controls the developmental integrity and cell cycle quiescence of multipotential hematopoietic progenitors.. Journal of immunology (Baltimore, Md. : 1950). 181(9):5885-94.. 2008.
Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 26(14):2390-3295.. 2008.
Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus.. Blood. 111(5):2615-20.. 2008.
Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo.. Genes & development. 22(12):1677-89.. 2008.
ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2.. Journal of leukocyte biology. 83(1):200-11.. 2008.
Phosphorylated ITIMs enable ubiquitylation of an inhibitory cell surface receptor.. Traffic (Copenhagen, Denmark). 9(2):267-79.. 2008.
Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity.. Cell stem cell. 3(6):611-24.. 2008.