Hematopoiesis; Leukemia; Myelodysplastic Syndromes; Alternative Splicing; Xenograft Model Antitumor Assays; Myelopoiesis
Stem Cell Center, Yale: Tissue Specific Stem Cells | Transcriptional Regulation of Stem and Progenitor Cells
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. 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; Myeloid differentiation; Leukemia; Myelodysplasia
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 AMLs. Mutations in SFs are not only recurrent in nature, affecting specific amino acid positions, but also mutually exclusive, i.e. patients carry mutations in only one splicing factor. This suggests a common mechanism in the pathogenesis of MDS. We employ structural, molecular biology, and in vivo techniques to determine disease mechanism and develop novel therapeutics.
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.
SRF in Hematopoiesis: Serum response factor (Srf) is a MADS-box transcription factor known to be critical for muscle differentiation.We uncovered novel roles for SRF in megakaryopoiesis and in neutrophil function. Ongoing studies determine the role of SRF in regulation of integrin homeostasis and function.
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 (email@example.com).
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.
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. Blood. 2016 Aug 19. pii: blood-2015-10-676452
Cooperative Activity of GABP with PU.1 or C/EBPε Regulates Lamin B Receptor Gene Expression, Implicating Their Roles in Granulocyte Nuclear Maturation.
Malu K, Garhwal R, Pelletier MG, Gotur D, Halene S, Zwerger M, Yang ZF, Rosmarin AG, Gaines P. J Immunol. 2016 Aug 1;197(3):910-22
SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.
Kim E.*, Llagan J.O.*, Liang Y.*, Daubner G.M. *, Lee S.W., Ramakrishnan A., Li Y., Chung Y.R., Micol J.B., Murphy M.E., Cho H., Kim M.K., Zebari A.S., Aumann S., Park C.Y., Buonamici S., Smith P.G., Deeg H.J., Lobry C., Aifantis I., Modis Y., Allain F.H.T., Halene S.#, Bradley R.K.#, Abdel-Wahab O.# Cancer Cell, 2015 May 11; 27(5): 617-630. * Co-first authors; # Co-senior authors
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. Blood 2014 May 8;123(19):3027-36. Epub 2014 Feb 26.
The regulatory role of serum response factor (SRF) pathway in neutrophil inflammatory response.
Taylor A, Halene S. Curr Opin Hematol. 2015 Jan;22(1):67-73; Epub 2014 Nov 13. PMID: 25402621. PMCID: PMC4374983.
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, and Flavell RA. Nat. Biotech. 2014 Apr; 32(4):364-72. Epub 2014 Mar 16.
MKL1 and MKL2 Play Redundant and Crucial Roles in Megakaryocyte Maturation and Platelet Formation.
Smith, E.C., Thon, J.N., Devine, M.T., Massaro, S.A., Lin, S., Halene, S., Italiano Jr., J.E., Krause, D.S. Blood 2012 Jul 17. Epub ahead of print
The Gaucher Disease Gene GBA1 Functions in Immune Regulation.
Liu, J., Halene, S., Yang, M., Iqbal, J., Yuen, T., Mehal, W.Z., Chuang, W.L., Jain, D., Sun, L., Zaidi, M., Mistry, P.K. Proc Natl Acad Sci USA 2012;109(25): 10018-23.
Role of RhoA Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes.
Gao Y, Smith E, Ker DE, Campbell P, Cheng E, Zhou S, Lin S, Wang L, Halene S, Krause DS. Dev Cell. 2012 Mar 13;22(3):573-84. Epub 2012 Mar 1
Serum Response Factor (SRF) is an essential transcription factor in megakaryocytic maturation.
Halene S, Gao Y, Hahn K, Massaro S, Lin S, Krause DS. Blood 2010 Sep 16; 116(11):1828-9. Epub 2010 Jun 4.
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 DS, Berliner N. Experimental Hematology, (2010) C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx
Different roles of Gß1 and Gß2 in neutrophil function revealed by gene expression silencing in primary mouse neutrophils
Zhang Y, Tang W, Jones MC, Xu W, Halene S, and Wu D J. Biol. Chem. 2010 Aug 6;285(32):24805-14. Epub 2010 Jun 4.
Sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab.
Halene S., A. Zieske, Berliner N. Nat Clin Pract Oncol. 3(3): 165-8, 2006
Gene Therapy Using Hematopoietic Stem Cells: Sisyphus Approaches the Crest.
Halene S, Kohn DB. Human Gen Therapy 11(9): 1259-67, 2000. PMID: 10890736
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 D, Robbins PB, Kohn DB. (1999) Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector.
Full List of PubMed Publications
- Wang R, Zeidan AM, Halene S, Xu X, Davidoff AJ, Huntington SF, Podoltsev NA, Gross CP, Gore SD, Ma X: Health Care Use by Older Adults With Acute Myeloid Leukemia at the End of Life. J Clin Oncol. 2017 Aug 7; 2017 Aug 7. PMID: 28783450
- Gaines P, Halene S: Rusty neutrophils in β-thalassemia: no traction! Blood. 2017 Jun 8. PMID: 28596437
- Joshi P, Halene S, Abdel-Wahab O: How do messenger RNA splicing alterations drive myelodysplasia? Blood. 2017 May 4; 2017 Mar 27. PMID: 28348147
- de Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, Obulkasim A, Dang J, Easton J, Verboon LJ, Mulder HL, Zimmermann M, Koss C, Gupta P, Edmonson M, Rusch M, Lim JY, Reinhardt K, Pigazzi M, Song G, Yeoh AE, Shih LY, Liang DC, Halene S, Krause DS, Zhang J, Downing JR, Locatelli F, Reinhardt D, van den Heuvel-Eibrink MM, Zwaan CM, Fornerod M, Gruber TA: Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet. 2017 Mar; 2017 Jan 23. PMID: 28112737
- 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 Res. 2017 Feb 17. PMID: 28003475
- 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. Sci Transl Med. 2017 Feb 1. PMID: 28148839
- Onuoha C, Arshad J, Astle J, Xu M, Halene S: Novel Developments in Leukopenia and Pancytopenia. Prim Care. 2016 Dec. PMID: 27866577
- 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 Oct 6; 2016 Aug 19. PMID: 27543436
- Malu K, Garhwal R, Pelletier MG, Gotur D, Halene S, Zwerger M, Yang ZF, Rosmarin AG, Gaines P: Cooperative Activity of GABP with PU.1 or C/EBPε Regulates Lamin B Receptor Gene Expression, Implicating Their Roles in Granulocyte Nuclear Maturation. J Immunol. 2016 Aug 1; 2016 Jun 24. PMID: 27342846
- Woodson KA, Lee Y, Gopalratnam K, Halene S: Adding insult to injury: autoimmune haemolytic anaemia complicated by pulmonary embolism. BMJ Case Rep. 2016 Jan 14; 2016 Jan 14. PMID: 26768839
- Sui Z, Nowak RB, Sanada C, Halene S, Krause DS, Fowler VM: Regulation of actin polymerization by tropomodulin-3 controls megakaryocyte actin organization and platelet biogenesis. Blood. 2015 Jul 23; 2015 May 11. PMID: 25964668
- 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 May 11. PMID: 25965569
- Malkhasyan K, Halene S, Lacy J: Oxaliplatin-related acute disseminated intravascular coagulation syndrome in a patient with metastatic colon cancer. Clin Colorectal Cancer. 2015 Mar; 2014 Oct 2. PMID: 25446051
- Halene S, Krause DS: Stem cell maintenance: aMPLe splicing choices. Blood. 2015 Feb 5. PMID: 25655452
- Taylor A, Halene S: The regulatory role of serum response factor pathway in neutrophil inflammatory response. Curr Opin Hematol. 2015 Jan. PMID: 25402621
- 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 May 8; 2014 Feb 26. PMID: 24574460
- 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. Nat Biotechnol. 2014 Apr; 2014 Mar 16. PMID: 24633240
- Guo S, Bai H, Megyola CM, Halene S, Krause DS, Scadden DT, Lu J: Complex oncogene dependence in microRNA-125a-induced myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2012 Oct 9; 2012 Sep 24. PMID: 23012470
- Smith EC, Thon JN, Devine MT, Lin S, Schulz VP, Guo Y, Massaro SA, Halene S, Gallagher P, Italiano JE Jr, Krause DS: MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation. Blood. 2012 Sep 13; 2012 Jul 17. PMID: 22806889
- Liu J, Halene S, Yang M, Iqbal J, Yang R, Mehal WZ, Chuang WL, Jain D, Yuen T, Sun L, Zaidi M, Mistry PK: Gaucher disease gene GBA functions in immune regulation. Proc Natl Acad Sci U S A. 2012 Jun 19; 2012 Jun 4. PMID: 22665763
- Gao Y, Smith E, Ker E, Campbell P, Cheng EC, Zou S, Lin S, Wang L, Halene S, Krause DS: Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes. Dev Cell. 2012 Mar 13; 2012 Mar 1. PMID: 22387001
- Wang R, Gross CP, Maggiore RJ, Halene S, Soulos PR, Raza A, Galili N, Ma X: Pattern of hypomethylating agents use among elderly patients with myelodysplastic syndromes. Leuk Res. 2011 Jul; 2010 Nov 9. PMID: 21067809
- Bajaj R, Xu F, Xiang B, Wilcox K, Diadamo AJ, Kumar R, Pietraszkiewicz A, Halene S, Li P: Evidence-based genomic diagnosis characterized chromosomal and cryptic imbalances in 30 elderly patients with myelodysplastic syndrome and acute myeloid leukemia. Mol Cytogenet. 2011 Jan 20; 2011 Jan 20. PMID: 21251322
- Halene S, Gao Y, Hahn K, Massaro S, Italiano JE Jr, Schulz V, Lin S, Kupfer GM, Krause DS: Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood. 2010 Sep 16; 2010 Jun 4. PMID: 20525922
- Zhang Y, Tang W, Jones MC, Xu W, Halene S, Wu D: Different roles of G protein subunits beta1 and beta2 in neutrophil function revealed by gene expression silencing in primary mouse neutrophils. J Biol Chem. 2010 Aug 6; 2010 Jun 4. PMID: 20525682
- 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. Exp Hematol. 2010 Feb; 2009 Dec 5. PMID: 19925846
- Wang R, Gross CP, Halene S, Ma X: Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes. Leuk Res. 2009 Dec; 2009 Mar 25. PMID: 19324411
- Wang R, Gross CP, Halene S, Ma X: Neighborhood socioeconomic status influences the survival of elderly patients with myelodysplastic syndromes in the United States. Cancer Causes Control. 2009 Oct; 2009 May 20. PMID: 19455395
- Halene S, Zieske A, Berliner N: Sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab. Nat Clin Pract Oncol. 2006 Mar. PMID: 16520806