Stephanie Halene, MD, PhD
Research & Publications
Biography
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Research Summary
Dr. Halene's laboratory studies hematopoiesis and myelopoiesis and in particular how abnormalities of the hematopoietic stem and progenitor cells lead to diseases with abnormal numbers and function of blood cells such as in Myelodysplastic Syndromes and Leukemia. The laboratory uses primary patient cells and murine models to study mechanisms of disease leading to myelodysplasia and acute myeloid leukemia with the ultimate goal to contribute to the development of novel treatments.
Specialized Terms: Hematopoiesis; Leukemia; Myelodysplasia; Myelodysplastic syndrome; Stem cells; Humanized mice; Xenotransplantation; PDX models; RNA biology; RNA splicing; RNA modifications
Extensive Research Description
Below find a description of our ongoing research projects in the Halene Lab:
Splicing Factor Mutations in Myeloid Malignancies: We seek to understand the role of mutations in splicing factors (SFs), present in nearly 50% of patient with MDS and a subset of patients with AMLs. Mutations in SFs are not only recurrent in nature, affecting specific amino acid positions, but also mutually exclusive; patients carry mutations in only one splicing factor. This suggests a common mechanism in the pathogenesis of MDS. We employ structural, molecular biology, and multi-omic approaches, and in vivo xenotransplantation to determine disease mechanism and develop novel therapeutics.
RNA modifications: We are interested how RNA modifications determine hematopoietic stem and progenitor cell function. We discovered that loss of METTL3 and the m6A RNA modification results in the aberrant formation of double stranded RNA and activation of a deleterious innate immune response. We treasure numerous collaborations within Yale's RNA Center to apply cutting edge technologies and deep understanding of RNA biology to hematologic disorders.
MDS/AML Co-clinical Models: MDS and AML are inherently difficult to study. They are heterogeneous diseases; only rare human cell lines have been successfully derived from patients’ MDS and few from patients with AML; hematopoietic and leukemic stem cells (HSC/LSC) do not grow in culture and MDS stem cells fail to efficiently engraft even in the best currently available mouse models. In collaboration with the Flavell laboratory we have developed the first highly efficient xenotransplantation model for MDS/AML in the humanized MISTRG mice amenable to drug treatments. We continue to improve upon this model to extend our studies to diseases of red cell production and the human immune system. We are collaborating with the Fan lab in the Yale Biomedical Engineering Department and the Grimes lab at Cincinnati Children's Hospital to generate multi-omic maps of MDS and AML in their microenvironments.
Hematology Tissue Bank: The Hematology Tissue Bank has been established to give researchers access to critical patient samples for the study of hematologic diseases. Should you wish to obtain samples for your research contact Dr. Halene via phone (203 785-7002) or e-mail (stephanie.halene@yale.edu).
Mouse Modeling Core (AMC) – Yale Cooperative Center of Excellence in Hematology (YCCEH): The Mouse Modeling Core, directed by Richard Flavell and Stephanie Halene, is part of the YCCEH with the goal to provide researchers with access to the latest technologies for hematologic studies in animal models. The AMC offers expertise, technical assistance, and mice for human-into-mouse xenotransplantation studies. It offers training and technical assistance in the study of hematopoiesis and benign hematologic questions in mice.
Coauthors
Research Interests
Hematopoiesis; Hematopoietic Stem Cells; Leukemia; Myelodysplastic Syndromes; RNA Splicing; Alternative Splicing; Xenograft Model Antitumor Assays
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Selected Publications
- Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature Reviews. Cardiology 2021, 18:194-209.
- Editorial: Do not lose focus on myeloid biology in the era of COVID-19.Halene S, Prebet T. Editorial: Do not lose focus on myeloid biology in the era of COVID-19. Current Opinion In Hematology 2021, 28:71-72.
- A neutrophil activation signature predicts critical illness and mortality in COVID-19.Meizlish ML, Pine AB, Bishai JD, Goshua G, Nadelmann ER, Simonov M, Chang CH, Zhang H, Shallow M, Bahel P, Owusu K, Yamamoto Y, Arora T, Atri DS, Patel A, Gbyli R, Kwan J, Won CH, Dela Cruz C, Price C, Koff J, King BA, Rinder HM, Wilson FP, Hwa J, Halene S, Damsky W, van Dijk D, Lee AI, Chun HJ. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Advances 2021, 5:1164-1177.
- Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells.Song Y, Shan L, Gbyli R, Liu W, Strowig T, Patel A, Fu X, Wang X, Xu ML, Gao Y, Qin A, Bruscia EM, Tebaldi T, Biancon G, Mamillapalli P, Urbonas D, Eynon E, Gonzalez DG, Chen J, Krause DS, Alderman J, Halene S, Flavell RA. Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells. Science (New York, N.Y.) 2021, 371:1019-1025.
- Functional Analysis of Human Hematopoietic Stem Cells In Vivo in Humanized Mice.Song Y, Gbyli R, Fu X, Halene S. Functional Analysis of Human Hematopoietic Stem Cells In Vivo in Humanized Mice. Methods In Molecular Biology (Clifton, N.J.) 2020, 2097:273-289.
- Humanized mice as preclinical models for myeloid malignancies.Gbyli R, Song Y, Halene S. Humanized mice as preclinical models for myeloid malignancies. Biochemical Pharmacology 2020, 174:113794.
- m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development.Gao Y, Vasic R, Song Y, Teng R, Liu C, Gbyli R, Biancon G, Nelakanti R, Lobben K, Kudo E, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA, Li HB, Tebaldi T, Halene S. m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development. Immunity 2020, 52:1007-1021.e8.
- Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, Baluha A, Bar N, Bona RD, Burns AJ, Dela Cruz CS, Dumont A, Halene S, Hwa J, Koff J, Menninger H, Neparidze N, Price C, Siner JM, Tormey C, Rinder HM, Chun HJ, Lee AI. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet. Haematology 2020, 7:e575-e582.
- Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms.Taylor J, Mi X, North KD, Binder M, Penson A, Lasho TL, Knorr K, Haddadin M, Liu B, Pangallo J, Benbarche S, Wiseman DH, Tefferi A, Halene S, Liang Y, Patnaik MM, Bradley RK, Abdel-Wahab O. Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms. Blood 2020, 136:1477-1486.
- A neutrophil activation signature predicts critical illness and mortality in COVID-19.Meizlish ML, Pine AB, Bishai JD, Goshua G, Nadelmann ER, Simonov M, Chang CH, Zhang H, Shallow M, Bahel P, Owusu K, Yamamoto Y, Arora T, Atri DS, Patel A, Gbyli R, Kwan J, Won CH, Dela Cruz C, Price C, Koff J, King BA, Rinder HM, Wilson FP, Hwa J, Halene S, Damsky W, van Dijk D, Lee AI, Chun H. A neutrophil activation signature predicts critical illness and mortality in COVID-19. MedRxiv : The Preprint Server For Health Sciences 2020.
- High-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue.Liu Y, Yang M, Deng Y, Su G, Enninful A, Guo CC, Tebaldi T, Zhang D, Kim D, Bai Z, Norris E, Pan A, Li J, Xiao Y, Halene S, Fan R. High-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue. Cell 2020, 183:1665-1681.e18.
- Circulating markers of angiogenesis and endotheliopathy in COVID-19.Pine AB, Meizlish ML, Goshua G, Chang CH, Zhang H, Bishai J, Bahel P, Patel A, Gbyli R, Kwan JM, Won CH, Price C, Dela Cruz CS, Halene S, van Dijk D, Hwa J, Lee AI, Chun HJ. Circulating markers of angiogenesis and endotheliopathy in COVID-19. Pulmonary Circulation 2020, 10:2045894020966547.
- A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies.Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X, Fu X, Gao Y, Zhao J, Podoltsev N, Xu M, Neparidze N, Wong E, Torres R, Bruscia EM, Kluger Y, Manz MG, Flavell RA, Halene S. A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies. Nature Communications 2019, 10:366.
- SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells.Liang Y, Tebaldi T, Rejeski K, Joshi P, Stefani G, Taylor A, Song Y, Vasic R, Maziarz J, Balasubramanian K, Ardasheva A, Ding A, Quattrone A, Halene S. SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells. Leukemia 2018, 32:2659-2671.
- 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science Translational Medicine 2017, 9.
- How do messenger RNA splicing alterations drive myelodysplasia?Joshi P, Halene S, Abdel-Wahab O. How do messenger RNA splicing alterations drive myelodysplasia? Blood 2017, 129:2465-2470.
- Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors.Yang J, Tanaka Y, Seay M, Li Z, Jin J, Garmire LX, Zhu X, Taylor A, Li W, Euskirchen G, Halene S, Kluger Y, Snyder MP, Park IH, Pan X, Weissman SM. Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors. Nucleic Acids Research 2017, 45:1281-1296.
- Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice.Saito Y, Ellegast JM, Rafiei A, Song Y, Kull D, Heikenwalder M, Rongvaux A, Halene S, Flavell RA, Manz MG. Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice. Blood 2016, 128:1829-1833.
- The regulatory role of serum response factor pathway in neutrophil inflammatory response.Taylor A, Halene S. The regulatory role of serum response factor pathway in neutrophil inflammatory response. Current Opinion In Hematology 2015, 22:67-73.
- SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, Li Y, Chung YR, Micol JB, Murphy ME, Cho H, Kim MK, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ, Lobry C, Aifantis I, Modis Y, Allain FH, Halene S, Bradley RK, Abdel-Wahab O. SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell 2015, 27:617-30.
- Development and function of human innate immune cells in a humanized mouse model.Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK, Manz MG, Flavell RA. Development and function of human innate immune cells in a humanized mouse model. Nature Biotechnology 2014, 32:364-72.
- SRF is required for neutrophil migration in response to inflammation.Taylor A, Tang W, Bruscia EM, Zhang PX, Lin A, Gaines P, Wu D, Halene S. SRF is required for neutrophil migration in response to inflammation. Blood 2014, 123:3027-36.
- Serum response factor is an essential transcription factor in megakaryocytic maturation.Halene S, Gao Y, Hahn K, Massaro S, Italiano JE, Schulz V, Lin S, Kupfer GM, Krause DS. Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood 2010, 116:1942-50.
- C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx.Halene S, Gaines P, Sun H, Zibello T, Lin S, Khanna-Gupta A, Williams SC, Perkins A, Krause D, Berliner N. C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx. Experimental Hematology 2010, 38:90-103.
- Gene therapy using hematopoietic stem cells: Sisyphus approaches the crest.Halene S, Kohn DB. Gene therapy using hematopoietic stem cells: Sisyphus approaches the crest. Human Gene Therapy 2000, 11:1259-67.
- Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector.Halene S, Wang L, Cooper RM, Bockstoce DC, Robbins PB, Kohn DB. Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector. Blood 1999, 94:3349-57.