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Your search keyword '"Ulrich G. Steidl"' showing total 13 results
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13 results on '"Ulrich G. Steidl"'

1. Prenatal vitamin D deficiency exposure leads to long-term changes in immune cell proportions

Author

Koki Ueda, Shu Shien Chin, Noriko Sato, Miyu Nishikawa, Kaori Yasuda, Naoyuki Miyasaka, Betelehem Solomon Bera, Laurent Chorro, Reanna Doña-Termine, Wade R. Koba, David Reynolds, Ulrich G. Steidl, Gregoire Lauvau, John M. Greally, and Masako Suzuki

Subjects
Medicine, Science
Abstract

Abstract Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term offspring also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the offspring. These findings imply that the differentiation properties of hematopoiesis act as long-term memories of prenatal vitamin D deficiency exposure in later life.

Published
2024
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4. Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations

Author

Gaurav S Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Srabani Sahu, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Ritesh Aggarwal, Sarah Aminov, Leya Schwartz, Violetta Steeples, Robert N Booher, Murali Ramachandra, Maria Samson, Milagros Carbajal, Kith Pradhan, Teresa V Bowman, Manoj M Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert K Bradley, Robert E Martell, Ulrich G Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T Starczynowski, and Amit Verma

Subjects
IRAK4, SF3B1, MDS, AML, CA4948, Emavusertib, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML. Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models. Funding: This work was supported by Cincinnati Children’s Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle’s Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).

Published
2022
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5. Outcomes of Autologous Stem Cell Transplantation for Relapsed DLBCL in Single Center Serving a Minority Population

Author

Tanim Jain, Abdul-Hamid Bazarbachi, Emma Rabinovich, Ahmed Abbasi, Kith Pradhan, Daniel K. Reef, Ryann Quinn, Hiba Narvel, Riya Patel, Rama Al Hamed, Astha Thakkar, Shafia Rahman, Alyssa De Castro, Felisha Joseph, Kailyn Gillick, Jennat Mustafa, Fariha Khatun, Amanda Lombardo, Latoya Townsend Nugent, Michelly Abreu, Nicole Chambers, Richard Elkind, Yang Shi, Yanhua Wang, Olga Derman, Xingxing Zang, Kira Gritsman, Ulrich G. Steidl, Mendel Goldfinger, Margaret McCort, Yoram Puius, Rachel Bartash, Noah Kornblum, Aditi Shastri, Ioannis Mantzaris, Lizamarie Bachier Rodriguez, Nishi Shah, Marina Konopleva, Christopher Nishimura, Dennis Cooper, Ira Braunschweig, Amit Verma, and R. Alejandro Sica

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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6. Molecular Characterization of Adult Acute Lymphoblastic Leukemia Identifies a Subgroup with Myeloid Mutations and Pre-Existing Clonal Hematopoiesis

Author

Caner Saygin, Jacob Stauber, Ibrahim Aldoss, Adam S. Sperling, Lachelle D. Weeks, Marlise R. Luskin, Todd C. Knepper, Pankhuri Wanjari, Peng Wang, Angela Lager, Jeremy Segal, Benjamin Kaumeyer, Sandeep Gurbuxani, Girish Venkataraman, Jason Xiaojun Cheng, Bartholomew Eisfelder, Oliver Bohorquez, Anand Ashwin Patel, Olatoyosi Odenike, Richard A. Larson, Lucy A. Godley, Daniel A. Arber, Benjamin L. Ebert, John M. Greally, Ulrich G. Steidl, Bijal D. Shah, and Wendy Stock

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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7. Author response: Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations

Author

Andrea Pellagatti, Gaurav S Choudhary, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Srabani Sahu, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Ritesh Aggarwal, Sarah Aminov, Leya Schwartz, Violetta Steeples, Robert N Booher, Murali Ramachandra, Maria Samson, Milagros Carbajal, Kith Pradhan, Teresa V Bowman, Manoj M Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert K Bradley, Robert E Martell, Ulrich G Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T Starczynowski, and Amit Verma

Published
2022
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8. Pre-Conditioning Easix Is Associated with Survival after Autologous Hematopoietic Stem Cell Transplant in Mature T-Cell Lymphomas

Author

Daniel K. Reef, John Wei, Alyssa De Castro, Felisha Joseph, Kailyn Gillick, Jennat Mustafa, Fariha Khatun, Amanda Lombardo, Latoya Townsend Nugent, Michelly Abreu, Nicole Chambers, Richard Elkind, Yang Shi, Yanhua Wang, Olga Derman, Kira Gritsman, Ulrich G. Steidl, Mendel Goldfinger, Noah Kornblum, Aditi Shastri, Ioannis Mantzaris, Lizamarie Bachier-Rodriguez, Nishi Shah, Marina Konopleva, Dennis Cooper, Ira Braunschweig, Amit Verma, and R. Alejandro Sica

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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9. Older Age and Neutrophil-to-Lymphocyte Ratio (NLR) Are Predictors of Illness Severity and COVID-Related Mortality in a Multiethnic Urban Cohort of Hematologic Neoplasms Patients: An Updated Analysis

Author

Angelica D'Aiello, Sumaira Zareef, Eleftheria Atalla, Ahmed Abbasi, Kith Pradhan, Amanda Lombardo, Fariha Khatun, Jennat Mustafa, Alyssa De Castro, Felisha Joseph, Kailyn Gillick, Astha Thakkar, Lauren C Shapiro, Shafia Rahman, Zhu Cui, Jesus D Gonzalez Lugo, Fiona Mienko, Numa Rahman, Robert Lopez, Heidi Chwan Ko, Amanda Podolski, Vikas Mehta, Sanjay Goel, Rafi Kabarriti, Joseph Sparano, Stuart Packer, David Lawrence Fernandes, Enrico Castelucci, Margarita Kushnir, Mark Chaitowitz, Luca Paoluzzi, Ulrich G. Steidl, Phaedon Zavras, Dennis Cooper, Marina Konopleva, Balazs Halmos, Ioannis Mantzaris, Noah Kornblum, Aditi Shastri, Lizamarie Bachier-Rodriguez, Kira Gritsman, Henny H. Billett, Rachel Bartash, Yoram Puius, Margaret McCort, Ira Braunschweig, Mendel Goldfinger, Amit Verma, and R. Alejandro Sica

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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10. Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS: Assessment of Leukemia Stem Cell Eradication By High-Resolution MRD Assay

Author

Ioannis Mantzaris, Mendel Goldfinger, David Levitz, Kateryna Fedorov, Karen Fehn, Nicole Chambers, Anne Munoz, Aradhika Dhawan, Joel Victor, Nishi Shah, Aditi Shastri, Noah Kornblum, R. Alejandro Sica, Kira Gritsman, Dennis Cooper, Mimi Kim, Evripidis Gavathiotis, Marina Konopleva, Amit Verma, Eric J. Feldman, and Ulrich G. Steidl

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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13. Mir-21 Mediates Hematopoietic Suppression in MDS by Activating TGF-b Signaling

Author

Tushar D. Bhagat, Li Zhou, Lubomir Sokol, Ioannis Mantzaris, Krishna Gundabolu, Shanisha A. K. Gordon, Yiting Yu, Sangeeta Nischal, Rahul Polineni, Carolina Schinke, Grigorios Chrysofakis, Amittha Wickrema, Andrea Pellagatti, Jacqueline Boultwood, Ulrich G Steidl, Gang Liu, Alan F List, Markus Bitzer, and Amit Verma

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Abstract 3813 Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. TGF-b is a hematopoietic inhibitory cytokine that has been indirectly linked to the pathogenesis of some subsets of MDS. We have shown that smad2, a component of the TGF- signaling pathway, is constitutively activated and upregulated in MDS progenitors (Blood, 112(8):3434; 2008). Since there is conflicting data about upregulation of TGF- b levels in MDS, we next sought to determine the molecular basis of TGF- b pathway activation in this disease. We observed that smad-7, a negative regulator of TGF- b receptor-I kinase, is markedly down regulated in MDS and leads overactivation of the receptor and subsequent smad2 phosphorylation / activation in this disease (Cancer Res, 71(3):955–63). In the present study we wanted to determine the cause of smad7 reduction in MDS. Since microRNA dysregulation has been reported in many malignancies, we explored the 3'UTR of the smad7 gene for putative microRNA binding sites and observed predicted mir-21 and mir-15/16 binding sites that were conserved across species. mir-21 was found to be elevated in a microarray screen in MDS (British J. Haem. 153(1):24–32) and was subsequently found by us to be significantly elevated by qPCR in MDS marrow samples when compared with age matched controls (TTest, N=11 in each group, P Value= 0.02). Luciferase reporters containing wild type and mutant 3' UTR of the smad7 gene were then used to determine whether mir21 was able to directly bind to the predicted sequence in the gene. Enforced expression of mir-21 was able to inhibit the wild type smad7 reporter expression and a mutation of 4 complementary residues in the 3'UTR led to abrogation of this effect, thus demonstrating direct effects of mir-21 on smad7 gene. To test the role of mir-21 in regulating TGF-b signaling in vivo, we used chemically modified, locked nucleic acid (LNA) inhibitors of mir-21. These were used in a TGF-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with the mir-21 inhibitor led to significant increases in RBC counts when compared to placebo (P value Disclosures: List: Celgene: Consultancy.

Published
2011
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