Pediatric Hematology Research

Pediatric Hematology Research
Head of the lab:
Dr. Orna Steinberg Shemer
Research team:
    Dr. Enosh Tomer    
    Dr. Lital Kalish-Philosoph    
    Yael Barhum    
    Almog Buganim    
Research Areas:
  1. The study of severe congenital neutropenia and cyclic neutropenia. Severe congenital neutropenia (SCN) is a mono-lineage bone marrow failure syndrome, characterized by early onset of neutropenia accompanied by severe infections. Bone marrow examination demonstrates promyelocytic maturation arrest. Cyclic neutropenia (CyN) is a congenital syndrome characterized by oscillations of the neutrophil counts with a nadir occurring every 21 days. Mutations in the ELANE gene can cause both diseases. We aim to identify key signaling pathways underlying SCN and CyN and their phenotypic differences, in order to establish better diagnostic criteria and novel therapeutic approaches. We use induced pluripotent stem cells (iPSCs) generated from patients with congenital neutropenias. Our iPSC system recapitulates the myeloid differentiation arrest found in bone marrows of patients with SCN and shows a difference in the myeloid differentiation potential between SCN and CyN.

  2. Elucidating the myeloid transformation processes in patients with congenital neutropenia. One severe complication of SCN is the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). An early event in this process involves acquisition of truncating mutations in the receptor of the granulocyte-colony stimulating factor (G-CSF), which are unique to patients with SCN. We aim to understand the signal transduction pathways triggered by the mutated G-CSF receptor in patients with congenital neutropenia in order to improve the diagnostic, preventive and therapeutic approaches for leukemia development. This study is performed on patients-derived iPSCs using the CRISPR/Cas9 gene editing system for the introduction of somatic mutations that are similar to those found in patients.

  3. Understanding the roles of GATA factors in normal and diseased erythropoiesis. The regulation of erythroid gene expression and erythroid differentiation is governed by the interplay between GATA1 and GATA2, that share a common DNA binding motif, and a key event in normal erythropoiesis is a "switch” in the expression of the two transcription factors. We aim to study the roles of GATA1 and GATA2 in initiating and driving red blood cell differentiation and their contribution to a rare anemia syndrome caused by mutations in GATA1. This study is performed in immortalized human CD34+ cells in combination with gene editing methods. 

Active grants

  • 2019-2021 Physician-Scientist grant. European Hematology Association
    Elucidating the pathophysiology of severe congenital neutropenia and the pathways involved in malignant transformation

  • 2019-2022 Physician-Scientist grant. Israel Science Foundation
    Elucidating the mechanisms of congenital anemia caused by germline GATA1s mutation: The roles of GATA2.

  • 2020-2023 Israel Innovation Authority The CRISPR-IL consortium – AI technologies for improving the efficiency and  accuracy of genome editing – with Dr. Yehudit Birger and Prof. Shai Izraeli.

  • 2020-2023 Co-PI (with Prof. Dani Offen) The Varda and Boaz Dotan Research Center in Hemato-Oncolog Novel method for selection of CD34+cells after editing Runx1 gene mutations.

  • 2020-2023 Co-PI (with Prof. Julia Skokowa, Tubingen, Germany) German Research Foundation (DFG)
    One gene, two phenotypes – understanding the pathomechanics and leukemia development in congenital neutropenia and cyclic neutropenia

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