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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:
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.
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.
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
Publications:
Steinberg O, Yacobovich J, Dgany O, Kodman Y, Livni G, Rachmel A, Stein J, Yaniv I, Tamary H. Prolonged course of familial hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2006 Dec;28(12):831-3.
Steinberg O, Gilad G, Dgany O, Krasnov T, Zoldan M, Laor R, Kapelushnik J, Gabriel H, Churi C, Stein J, Yaniv I, Tamary H. Congenital amegakaryocytic thrombocytopenia-3 novel c-MPL mutations and their phenotypic correlations. J Pediatr Hematol Oncol. 2007 Dec;29(12):822-5.
Steinberg-Shemer O, Tamary H. Think about hemoglobinopathies. Isr Med Assoc J. 2014 Dec;16(12):785-6.
Giani FC, Fiorini C, Wakabayashi A, Ludwig LS, Salem RM, Jobaliya CD, Regan SN, Ulirsch JC, Liang G, Steinberg-Shemer O, Guo MH, Esko T, Tong W, Brugnara C, Hirschhorn JN, Weiss MJ, Zon LI, Chou ST, French DL, Musunuru K, Sankaran VG. Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells. Cell Stem Cell. 2016 Jan 7;18(1):73-78.
Steinberg-Shemer O, Keel S, Dgany O, Walsh T, Noy-Lotan S, Krasnov T, Yacobovich J, Quarello P, Ramenghi U, King MC, Shimamura A, Tamary H. Diamond Blackfan Anemia: A Nonclassical Patient With Diagnosis Assisted by Genomic Analysis. J Pediatr Hematol Oncol. 2016 Oct;38(7):e260-2.
Yacobovich J, Abu-Ahmed S, Steinberg-Shemer O, Goldberg T, Cohen M, Tamary H. Anti-D treatment for pediatric immune thrombocytopenia: Is the bad reputation justified? Semin Hematol. 2016 Apr;53 Suppl 1:S64-6.
Gilad O, Steinberg-Shemer O, Dgany O, Krasnov T, Nevo M, Noy-Lotan S, Rabinowicz R, Amitai N, Ben-Dor S, Yaniv I, Yacobovich J, Tamary H. Molecular diagnosis of α-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562.
Steinberg-Shemer O, Ulirsch JC, Noy-Lotan S, Krasnov T, Attias D, Dgany O, Laor R, Sankaran VG, Tamary H. Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia. Cold Spring Harb Mol Case Stud. 2017 Nov;3(6).
Tanous O, Steinberg Shemer O, Yacobovich J, Zoldan M, Horovitz Y, Yaniv I, Rabizadeh E, Tamary H, Nakav S, Lahav J. Evaluating platelet function disorders in children with bleeding tendency – A single center study. Platelets. 2017 Nov;28(7):676-681.
Seo A, Steinberg-Shemer O, Unal S, Casadei S, Walsh T, Gumruk F, Shalev S, Shimamura A, Akarsu NA, Tamary H, King MC. Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1. Proc Natl Acad Sci U S A. 2018 May 15;115(20):5241-5246.
Shefer Averbuch N, Steinberg-Shemer O, Dgany O, Krasnov T, Noy-Lotan S, Yacobovich J, Kuperman AA, Kattamis A, Ben Barak A, Roth-Jelinek B, Chubar E, Shabad E, Dufort G, Ellis M, Wolach O, Pazgal I, Abu Quider A, Miskin H, Tamary H. Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias. Eur J Haematol. 2018 Sep;101(3):297-304.
Steinberg-Shemer O, Tamary H. Gray platelet syndrome mimicking atypical autoimmune lymphoproliferative syndrome: the key is in the blood smear. Blood. 2018 Jun 14;131(24):2737.
Steinberg-Shemer O, Yacobovich J, Cohen M, Cabantchik IZ, Tamary H. Labile plasma iron as an indicator of patient adherence to iron chelation treatment. Blood Cells Mol Dis. 2018 Jul;71:1-4.
Steinberg-Shemer O, Goldberg TA, Yacobovich J, Levin C, Koren A, Revel-Vilk S, Ben-Ami T, Kuperman AA, Shkalim Zemer V, Toren A, Kapelushnik J, Ben-Barak A, Miskin H, Krasnov T, Noy-Lotan S, Dgany O, Tamary H. Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population. Haematologica. 2019 Sep 26.
Barg AA, Toren A, Tamary H, Yacobovich J, Steinberg-Shemer O, Gilad O, Goldstein G, Miskin H, Revel-Vilk S, Rosenbeg N, Kenet G, Zemer VS. Essential thrombocythemia A retrospective case series. Pediatr Blood Cancer. 2020 May;67(5):e28183.
Gilad O, Steinberg-Shemer O, Dgany O, Krasnov T, Noy-Lotan S, Tamary H, Yacobovich J. Alpha-Thalassemia Carrier due to -α3.7 Deletion: Not So Silent. Acta Haematol. 2020 Jan 14:1-6.
Goldberg L, Simon AJ, Rechavi G, Lev A, Barel O, Kunik V, Toren A, Schiby G, Tamary H, Steinberg-Shemer O, Somech R. Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene. Pediatr Blood Cancer. 2020 Jun;67(6):e28237.
Steinberg-Shemer O, Tamary H. Impact of Next-Generation Sequencing on the Diagnosis and Treatment of Congenital Anemias. Mol Diagn Ther. 2020 Jun 17.
Yacobovich J, Barzilai-Birenboim S, Steinberg-Shemer O, Stark P, Pazgal I, Tamary H. Splenectomy in childhood for non-malignant haematologic disorders – long-term follow-up shows minimal adverse effects. Br J Haematol. 2020 Apr 28.
Sims MC, Mayer L, Collins J, Bariana T, Megy K, Lavenu-Bombled C, Seyres D, Kollipara L, Burden F, Greene D, Lee D, Rodriguez-Romera A, Alessi MC, Astle WJ, Bahou W, Bury L, Chalmers E, Da Silva R, De Candia E, Deevi SVV, Farrow S, Gomez K, Grassi L, Greinacher A, Gresele P, Hart DP, Hurtaud MF, Kelly A, Kerr R, Le Quellec S, Leblanc TM, Leinøe EB, Mapeta RP, McKinney H, Michelson AD, Morais S, Nugent DJ, Papadia S, Park SJ, Pasi J, Podda GM, Poon MC, Reed R, Sekhar M, Shalev H, Sivapalaratnam S, Steinberg-Shemer O, Stephens JC, Tait RC, Turro E, Wu JK, Zieger BMH, BioResource N, Kuijpers TW, Whetton AD, Sickmann A, Freson K, Downes K, Erber W, Frontini M, Nurden P, Ouwehand WH, Favier R, Guerrero JA. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood. 2020 Jul 21:blood.2019004776.
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