New publication from the Guo Lab - Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris A Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip M Galbo Jr, Dayle Q Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo. MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state. Nat Cell Biol. 2023 Jan 5. doi: 10.1038/s41556-022-01045-0.
“Efficient metastasis relies on dynamic switches between epithelial and mesenchymal cell states. Recent work has shown that cancer cells with a hybrid epithelial-mesenchymal (EMT) property are highly metastatic. However, the mechanisms that allow cancer cells to acquire the hybrid EMT state are poorly understood. In this study, we discovered how MLL3 loss facilitates the induction of the hybrid EMT state and promotes metastasis.”
New publication from the Fyodorov and Skoultchi Labs - Andreyeva, E. N., A. V. Emelyanov, M. Nevil, L. Sun, E. Vershilova, C. A. Hill, M. C. Keogh, R. J. Duronio, A. I. Skoultchi and D. V. Fyodorov (2022). "Drosophila SUMM4 complex couples insulator function and DNA replication control." Elife 11. DOI: 10.7554/eLife.81828
“In this study, we introduce a novel technique that combines FPLC purification steps with shotgun quantitative proteomics to identify stable protein complexes and use it to identify a complex (SUMM4) of an insulator protein Mod(Mdg4) and a SNF2-like ATP-dependent chromatin remodeling protein SUUR (Suppressor of Under-Replication). Mod(Mdg4) and SUUR are required both for the activity of gypsy insulator elements and for delaying endoreplication of heterochromatic domains in Drosophila polytene chromosomes. Our results suggest that insulators and insulator proteins can directly regulate replication timing by creating a physical barrier to replication fork progression.”
New publication from the Aguirre-Ghiso Lab - Ana Rita Nobre, Erica Dalla, Jihong Yang, Xin Huang, Lena Wullkopf, Emma Risson, Pedram Razghandi, Melisa Lopez Anton, Wei Zheng, Jose A. Seoane, Christina Curtis, Ephraim Kenigsberg, Jianlong Wang & Julio A. Aguirre-Ghiso. ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung. Nature Cancer. 01 September 2022. PMID: 36050483 DOI: 10.1038/s43018-022-00424-8. [Nature]
“By identifying the role of a key pluripotency factor in driving mesenchymal-like gene expression programs to induce tumor dormancy, in this study Aguirre-Ghiso and colleagues highlight the plastic manner in which aspects of pluripotency, differentiation, epithelial-to-mesenchymal transition and dormancy are orchestrated during early tumor cell dissemination.”
New publication from the Will Lab - Ujunwa Cynthia Okoye-Okafor, Komal K. Javarappa, Dimitrios Tsallos, Joseph Saad, Daozheng Yang, Chi Zhang, Lumie Benard, Victor J. Thiruthuvanathan, Sally Cole, Stephen Ruiz, Madhuri Tatiparthy, Gaurav Choudhary, Stefanie DeFronzo, Boris A. Bartholdy, Celine Pallaud, Pedro Marques Ramos, Aditi Shastri, Amit Verma, Caroline A. Heckman, Britta Will. Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine. J Exp Med. 7 November 2022; 219 (11): e20212228. doi: https://doi.org/10.1084/jem.20212228.
“Therapy with DNA hypomethylating agents is often associated with cypopenias. In this study, we identify and therapeutically mitigate a molecular mechanism of action leading to critically reduced platelet generation in patients with myelodysplastic syndrome under azacitidine therapy.”
New publication from the Will Lab - Maria M. Aivalioti; Boris A. Bartholdy; Kith Pradhan; Tushar D. Bhagat; Aliona Zintiridou; Jong Jin Jeong; Victor J. Thiruthuvanathan; Mario Pujato; Aditi Paranjpe; Chi Zhang; Ross L. Levine; Aaron D. Viny; Amittha Wickrema; Amit Verma; Britta Will. PU.1-Dependent Enhancer Inhibition Separates Tet2-Deficient Hematopoiesis from Malignant Transformation. Blood Cancer Discov OF1–OF24. PMID: 35820129 DOI: 10.1158/2643-3230.BCD-21-0226. [aacrjournals.org][Pubmed]
“Mechanisms driving malignant transformation of hematopoietic stem cells during aging have been incompletely defined. In this new study, we report moderately impaired PU.1 mRNA expression as a biological modality predisposing Tet2-deficient hematopoietic stem and progenitor cells to malignant transformation. Our study furthermore uncovers a methylation-sensitive PU.1 gene network as a common feature of myeloid leukemia potentially allowing for the identification of patients at risk for malignant transformation.”
New publication from the Stanley Lab - Matsumoto K, Kumar V, Varshney S, Nairn AV, Ito A, Pennarubia F, Moremen KW, Stanley P, Haltiwanger RS. Fringe GlcNAc-transferases differentially extend O-fucose on endogenous NOTCH1 in mouse activated T cells. J Biol Chem. 2022 Jul;298(7):102064. doi: 10.1016/j.jbc.2022.102064. Epub 2022 May 25.
“In this paper we show using mass spectrometry that endogenous NOTCH1 isolated from activated T cells from mouse spleen is modified by each Fringe GlcNAc-transferase expressed alone, and that maximal modification by Fringe requires all three Fringes – LFNG, MFNG and RFNG. This is the first analysis of O-glycans on physiologically-modified NOTCH1 in mammals.”
New publication from the Schildkraut Lab - Twayana S, Bacolla A, Barreto-Galvez A, De-Paula RB, Drosopoulos WC, Kosiyatrakul ST, Bouhassira EE, Tainer JA, Madireddy A, Schildkraut CL. Translesion polymerase eta both facilitates DNA replication and promotes increased human genetic variation at common fragile sites. Proc Natl Acad Sci U S A. 2021. Nov 30;118(48):e2106477118. doi: 10.1073/pnas.2106477118. PMID: 34815340.
“Translesion polymerase eta: Role in DNA damage repair at chromosomal fragile sites.”
New publication from the Ye Lab - Yasunori Kogure, Takuro Kameda, Junji Koya, Makoto Yoshimitsu, Kisato Nosaka, Jun-Ichirou Yasunaga, Yoshitaka Imaizumi, Mizuki Watanabe, Yuki Saito, Yuta Ito, Marni B McClure, Mariko Tabata, Sumito Shingaki, Kota Yoshifuji, Kenichi Chiba, Ai Okada, Nobuyuki Kakiuchi, Yasuhito Nannya, Ayako Kamiunten, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Akira Kitanaka, Michihiro Hidaka, Nobuaki Nakano, Atae Utsunomiya, R Alejandro Sica, Ana Acuna-Villaorduna, Murali Janakiram, Urvi A Shah, Juan Carlos Ramos, Tatsuhiro Shibata, Kengo Takeuchi, Akifumi Takaori-Kondo, Yasushi Miyazaki, Masao Matsuoka, Kenji Ishitsuka, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, B Hilda Ye*, Kazuya Shimoda*, Keisuke Kataoka*. *Communication authors. Whole-genome landscape of adult T-cell leukemia/lymphoma. Blood. 2021 Oct 25;blood.2021013568. doi: 10.1182/blood.2021013568.
“Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoma that phenotypically resembles regulatory T cells (Treg). In this study, whole-genome sequencing (WGS) of 150 ATL cases revealed the overarching landscape of genetic alterations in ATL. We discovered that one third of ATL patients carry loss-of-function alterations targeting the CIC long isoform, which can restrain Treg expansion in a mouse model. In all, 55 ATL driver mutations were found, and two molecular groups of ATL were described with district clinical and genetic characteristics.”
New publication from the Kielian Lab - Das, P.K. and M. Kielian. (2021). The Enigmatic Capsid Protein of an Encephalitic Rubivirus. (2021) J. Virol. 95: e02294-20.
“In this study, we bioinformatically looked into the capsid protein of novel Rustrela Virus, a close relative of the human Rubella virus with potential for zoonotic spillover to humans. We found that the capsid protein, which packages the infectious viral RNA, may be longer at its N-terminus than previously reported by Bennett et al (Nature 2020). Our data raise interesting questions about the capsid protein of this virus and demonstrate that we do not fully understand if/how the additional N-terminal fragment is translated in the virus-infected cell.”
New publication from the Frenette Lab - Xin Gao., Dachuan Zhang, Chunliang Xu, Huihui Li, Kathleen M. Caron & Paul S. Frenette. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature. Published online Dec 23 2020.
“Pain-sensing nerve cells can mobilize blood stem cells in mice, with a component of chilli peppers being one stimulus. The finding holds the promise of improving procedures for stem-cell transplantation.”
New publication from the Kitsis Lab - Wendy M. McKimpson, Yun Chen, James A. Irving, Min Zheng, Jeremy Weinberger, Wilson Lek, Wen Tan, Zenia Tiang, Alistair M.Jagger, Streamson C. Chua Jr. Jeffrey E. Pessin, Roger S.-Y. Foo, David A. Lomas, Richard N. Kitsis. Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.
Dev Cell. 2021 Feb 25;S1534-5807(21)00122-2.
doi: 10.1016/j.devcel.2021.02.011.
“We show that the cell death inhibitor ARC translocates from the cytoplasm to the nucleus during diabetes to paradoxically activate the deaths of pancreatic beta-cells, the cells that make insulin. The mechanism involves transcriptional downregulation in the expression and secretion of multiple serpins, serine protease inhibitors, not previously known to be synthesized in beta-cells. Loss of the serpin alpha 1-antitrypsin in the extracellular space unleashes elastase which severs contacts of beta-cells with the extracellular matrix thereby activating beta-cell death. Administration of the FDA-approved drug alpha-1 antitrypsin attenuates the progression of diabetes in a preclinical mouse model.”
New publication from the Steidl Lab - Ueda K, Kumari R, Schwenger E, Wheat JC, Bohorquez O, Narayanagari SR, Taylor SJ, Carvajal LA, Pradhan K, Bartholdy B, Todorova TI, Goto H, Sun D, Chen J, Shan J, Song Y, Montagna C, Pellagatti A, Boultwood J, Xiong S, Lozano G, Verma A, Steidl U. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell. 2021 Mar 4 [epub ahead of print]; doi.org/10.1016/j.ccell.2021.02.006.
“In this study we show that MDMX overexpression induces preleukemic-to-AML transition in 5 different mouse genetic models. MDMX causes preleukemic-to-AML transition by p53-independent activation of β-Catenin through a CK1α-mediated mechanism. MDMX overexpression strongly correlates with progression to AML in patients with MDS.”
New publication from the Skoultchi Lab - Michael A. Willcockson, Sean E. Healton, Cary N. Weiss, Boris A. Bartholdy, et al. H1 histones control the epigenetic landscape by local chromatin compaction. Nature, published online December 9, 2020. https://www.nature.com/articles/s41586-020-3032-z.
“Experiments using a conditional triple-knockout mouse strain show that histone H1 regulates the activity of chromatin domains by controlling chromatin compaction, genome architecture and histone methylation.”
New publication from the Skoultchi Lab - Nevin Yusufova et al. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature, published online December 9, 2020. https://www.nature.com/articles/s41586-020-3017-y.
“Mutations in histone H1 induce the remodelling of chromatin architecture to a more relaxed state, which leads to malignant transformation through changes in histone modifications and the expression of stem cell genes.”
New publication from the Schildkraut Lab - Drosopoulos, W.C., Deng, Z., Twayana, S., Kosiyatrakul, S.T., Vladimirova, O., Lieberman, P.M., Schildkraut, C.L. TRF2 Mediates Replication Initiation within Human Telomeres to Prevent Telomere Dysfunction.
Cell Reports 33:108379
“Drosopoulos et al. report that active recruitment of ORC2 to telomeres by TRF2 leads to formation of functional DNA replication origins in human telomeres. These origins provide an important mechanism for avoiding telomere repeat loss and dysfunction and rescuing challenged telomere replication.”
New publication from the Kielian Lab - R. S. Brown, D.G. Anastasakis, M. Hafner, and M. Kielian. Multiple Capsid Protein Binding Sites Mediate Selective Packaging of the Alphavirus Genomic RNA. Nature Communications, 11:4693. DOI: https://www.nature.com/articles/s41467-020-18447-z.
“Alphaviruses need to selectively package genomic viral RNA for transmission, but the packaging mechanism remains unclear. We combine PAR-CLIP with biotinylated capsid protein (Cp) retrieval and identify multiple Cp binding sites on genomic viral RNA that promote virion formation and specific nucleocapsid assembly.”
New publication from the Stanley Lab - Ayodele Akintayo, Joshua Mayoral, Masahiro Asada, Jian Tang, Subha Sundaram, Pamela Stanley. Point Mutations that Inactivate MGAT4D-L, an Inhibitor of MGAT1 and Complex N-Glycan Synthesis. DOI: 10.1074/jbc.RA120.014784
“In this paper we show that the inhibitor of complex N-glycan synthesis MGAT4D-L can be inactivated by two independent point mutations that do not inhibit binding to MGAT1 or Golgi localization.”
New publication from the Query Lab - Wei Shao, Zhan Ding, Zeng-Zhang Zheng, Ji-Jia Shen, Yu-Xian Shen, Jia Pu, Yu-Jie Fan, Charles C Query, Yong-Zhen Xu. Nucleic Acids Res. 2020 Jun 19;48(11):5799-5813. doi: 10.1093/nar/gkaa311. PMID: 32605989. DOI: 10.1128/mBio.01382-20
Components of the TBP-binding module of the transcriptional SAGA complex (Spt8p and Spt3p) serve as genetic suppressors of defects in the RNA-dependent ATPase Prp5p (a component of the U2 snRNP that is required for pre-spliceosome assembly and splicing proofreading). Multiple genetic and physical interactions between the SAGA complex and U2 snRNP reveal a new facet of co-transcriptional splicing.”
New publication from the Guo Lab - Christin JR, Wang C, Chung CY, Liu Y, Dravis C, Tang W, Oktay MH, Wahl GM, Guo W.. Stem Cell Determinant SOX9 Promotes Lineage Plasticity and Progression in Basal-like Breast Cancer. Cell Rep. 2020 Jun 9;31(10):107742. doi: 10.1016/j.celrep.2020.107742. PMID: 32521267.
Inactivation of tumor suppressors p53 and Rb upregulates the mammary stem cell factor Sox9 to promote lineage plasticity and the progression of DCIS to invasive tumors.
New publication from the Steidl, Singer, Bergman, and Skoultchi Labs - Wheat JC, Sella Y, Willcockson M, Skoultchi AI, Bergman A, Singer RH, Steidl U.. Single-molecule imaging of transcription dynamics in somatic stem cells. Nature. 2020 Jun 24. doi: 10.1038/s41586-020-2432-4. Online ahead of print. PMID: 32581360.
Single-molecule fluorescence in situ hybridization and live-cell imaging are used to study the contribution of transcriptional noise to stem cell heterogeneity, revealing that stochastic transcription dynamics are conducive to concomitant stem-cell maintenance and tissue homeostasis.
New publication from the Stanley Lab - Barnali Biswas, Frank Batista, Ayodele Akintayo, Jennifer Aguilan, Pamela Stanley. Transgenic Rescue of Spermatogenesis in Males With Mgat1 Deleted in Germ Cells. Front Cell Dev Biol 2020 Apr 2;8:212. doi: 10.3389/fcell.2020.00212. eCollection 2020.
Deletion of Mgat1 in spermatogonia prevents the synthesis of complex N-glycans in germ cells and causes a total block in spermatogenesis, which shows can be fully rescued by expressing a Mgat1 transgene in spermatogonia, but not by expression in spermatocytes or spermatids.
New publication from the Skoultchi Lab - Sean E. Healton, Hugo D. Pinto, Laxmi N. Mishra, Gregory A. Hamilton, Justin C. Wheat, Kalina Swist-Rosowska, Nicholas Shukeir, Yali Dou, Ulrich Steidl, Thomas Jenuwein, Matthew J. Gamble, and Arthur I. Skoultchi. H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction. Proc Natl Acad Sci USA June 23, 2020 117 (25) 14251-14258; https://doi.org/10.1073/pnas.1920725117.
This study shows that H1 linker histones are critical for silencing repetitive DNA sequences by promoting repressive lysine methylation of H3 histone and further compacting the repetitive sequences into compact chromatin structure.
New publication from the Stanley Lab - Akintayo A, Liang M, Bartholdy B, Batista F, Aguilan J, Prendergast J, Sabrin A, Sundaram S, Stanley P. The Golgi Glycoprotein MGAT4D is an Intrinsic Protector of Testicular Germ Cells From Mild Heat Stress. Sci Rep. 2020 Feb 7;10(1):2135. doi: 10.1038/s41598-020-58923-6.
A novel inhibitor of branched N-glycan synthesis previously identified in the Stanley lab is shown in this paper to protect male germ cells from heat stress. It is the first intrinsic protector of germ cells from apoptosis caused by increased temperature of the testes.
New publication from the Schildkraut Lab - Drosopoulos WC, Vierra DA, Kenworthy CA, Coleman RA and Schildkraut CL. Dynamic Assembly and Disassembly of the Human DNA Polymerase δ Holoenzyme on the Genome In Vivo. (2020) Cell Reports 30:1329-1341. PMID:32023453 DOI:10.1016/j.celrep.2019.12.101.
Drosopoulos et al. report human Pol δ holoenzyme assembly and disassembly on the genome in vivo are highly dynamic and ordered. They find that assembly and disassembly of the Pol δ holoenzyme complex follow a predominant pathway in vivo, with alternate pathways also observed.
New publication from the Stanley Lab - Varshney S, Wei H, Batista F, Nauman M, Sundaram S, Siminovitch K, Tanwar A, and Stanley P. A modifier in the 129S2/SvPasCrl genome is responsible for the viability of Notch1[12f/12f] mice. BMC Dev Biol. 2019; 19: 19. Published online 2019 Oct 7. doi: 10.1186/s12861-019-0199-3.
Mice with NOTCH1 lacking fucose in the ligand binding domain have T and B cell development defects on a mixed genetic background (Ge and Stanley, PNAS, 2008) but we now show they are embryonic lethal on a C57BL/6J background, revealing a modifier that may now be identified.
New publication from the Skoultchi Lab - Willcockson MA, Taylor SJ, Ghosh S, Healton SE, Wheat JC, Wilson TJ, Steidl U, Skoultchi AI.Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation. Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17841-17847. doi: 10.1073/pnas.1901122116. Epub 2019 Aug 20. PMID: 31431533.
This study shows that the transcription factor Runx1 regulates expression of Pu.1 through an upstream regulatory element (“URE”) in erythroid progenitors to promote their proliferation and block their terminal differentiation into red blood cells.
New publication from the Kielian Lab - Wan JJ, Ooi YS, Kielian M. Mechanism of Tetherin Inhibition of Alphavirus Release. J Virol. 2019 Mar 21;93(7). pii: e02165-18. doi: 10.1128/JVI.02165-18. Print 2019 Apr 1.
While the anti-viral host factor tetherin can mediate virus endocytic uptake and clearance, this has not been observed to be required for restriction. Here we show that efficient tetherin inhibition of alphavirus release requires efficient tetherin endocytosis.
New publication from the Ye Lab - Chung EYL, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, Ren X, Pradhan K, Bartholdy B, Wei X, Zou Y, Zhang J, Ogawa S, Steidl U, Zang X, Verma A, Janakiram M, Ye BH. PAK kinase inhibition has therapeutic activity in novel preclinical models of Adult T-cell Leukemia/Lymphoma. Clin Cancer Res. 2019 Mar 12. PMID: 30862694 DOI: 10.1158/1078-0432.CCR-18-3033.
Adult T-cell leukemia/lymphoma (ATLL) is an extremely aggressive T cell malignancy that features remarkable chemoresistance and yet no effective targeted therapy currently exists for this disease. In this study, we discovered that PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Results based on cell line and patient-derived xenograft models suggest that PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
New publication from the Kielian Lab - Emily Byrd and Margaret Kielian. The Alphavirus E2 Membrane-Proximal Domain Impacts Capsid Interaction and Glycoprotein Lattice Formation. Journal of Virology 2019 Volume 93 Issue 4 e01881-18. doi: 10.1128/JVI.01881-18.
This paper demonstrates that a region of the alphavirus E2 membrane protein promotes virus budding though its effects on both the formation of the external glycoprotein lattice and interactions with the internal capsid protein shell.
New publication from the Steidl Lab - Jiahao Chen, Yun-Ruei Kao, Daqian Sun, Tihomira I. Todorova, David Reynolds, Swathi-Rao Narayanagari, Cristina Montagna, Britta Will, Amit Verma & and Ulrich Steidl. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nature Medicine. 2018 Dec 3; doi.org/10.1038/s41591-018-0267-4.
This longitudinal study of patients with MDS who later progressed to AML demonstrates the existence of immunophenotypically and functionally defined pre-MDS stem cells, and shows that MDS and secondary AML evolve largely independently and in a parallel manner. Our study reveals that MDS stem cell compartments with an unexpectedly high subclonal mutational diversity provide the basis for disease development and progression, and thereby challenges the current linear divergence model of leukemia evolution.
New publication from the Steidl and Will Labs - Yun-Ruei Kao, Jiahao Chen, Swathi-Rao Narayanagari, Tihomira I. Todorova, Maria M. Aivalioti, Mariana Ferreira, Pedro M. Ramos, Celine Pallaud, Ioannis Mantzaris, Aditi Shastri, James B. Bussel, Amit Verma, Ulrich Steidl, Britta Will. Thrombopoietin receptor–independent stimulation of hematopoietic stem cells by eltrombopag. Science Translational Medicine 12 Sep 2018: Vol. 10, Issue 458, eaas9563
DOI: 10.1126/scitranslmed.aas9563.
ONLINE COVER The Iron in the Fire of Hematopoiesis. This image shows molten iron, representing the focus of a study by Kao et al., where the authors linked the role of iron metabolism to unexpected benefits of a drug that bolsters platelets. Eltrombopag was designed as a thrombopoietin receptor agonist to stimulate platelet recovery for patients with thrombocytopenia, but clinical experience has shown that it also stimulates hematopoietic stem cell function in general, prompting a search for the underlying mechanism. The authors determined that in addition to its effects on the thrombopoietin receptor, eltrombopag chelates intracellular iron in hematopoietic stem cells, thus stimulating their activity.
New publication from the Ye Lab - Shah UA, Chung EY, Giricz O, Pradhan K, Kataoka K, Gordon-Mitchell S, Bhagat TD, Mai Y, Wei Y, Ishida E, Choudhary GS, Joseph A, Rice R, Gitego N, Parrish C, Bartenstein M, Goel S, Mantzaris I, Shastri A, Derman O, Binder A, Gritsman K, Kornblum N, Braunschweig I, Bhagat C, Hall J, Graber A, Ratner L, Wang Y, Ogawa S, Verma A, Ye BH, Janakiram M. North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies. Blood. 2018 Aug 13. pii: blood-2018-01-824607. doi: 10.1182/blood-2018-01-824607. [Epub ahead of print] PMID: 30104217.
Adult T-cell leukemia/lymphoma (ATLL) is a rare but extremely aggressive cancer, associated with a dismal outcome and lack of effective therapies. In this study, we demonstrate that ATLL patients diagnosed in North American have a distinct genomic landscape compared to the Japanese cohort. In particular, North American is characterized by a much higher frequency of prognostic epigenetic mutations and is targetable preclinically with DNA de-methylation drugs.
New publication from the Steidl Lab - Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony Debré I, Narayanagari SR, Carvajal LA, Leite J, Piperdi Z, Pendurti G, Mantzaris I, Paietta E, Verma A, Gritsman K, Steidl U. IL1RAP potentiates multiple oncogenic signaling pathways in AML. J Exp Med. 2018; doi.org/10.1084/jem.20180147.
IL1RAP is an emerging target for AML therapy. Studying its cell-intrinsic function revealed that IL1RAP interacts with and amplifies signaling through c-KIT and FLT3 in AML cells. This novel promiscuous role of IL1RAP in AML has implications for therapeutic targeting.
New publication from the Steidl Lab - Carvajal LA, Ben-Neriah D, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, Narayanagari SR, Wheat JC, Todorova TI, Mitchell KM, Kenworthy C, Guerlavais V, Annis DA, Bartholdy B, Will B, Anampa JD, Mantzaris I, Aivado M, Singer RH, Coleman RA, Verma A, Steidl U. Dual inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia. Sci Transl Med. 2018 Apr 11; 10:eaao3003.
This work shows that dual inhibition of MDMX and MDM2 by an α-helical p53-stapled peptide (ALRN-6924) results in robust antitumor activity in acute myeloid leukemia.
New publication from the Ye Lab - Kuo PY, Jatiani SS, Rahman AH, Edwards D, Jiang Z, Ahr K, Perumal D, Leshchenko VV, Brody J, Shaknovich R, Ye BH, Parekh S. SOX11 augments BCR signaling to drive MCL-like tumor development. Blood. 2018 Apr 3. pii: blood-2018-02-832535. doi: 10.1182/blood-2018-02-832535. PMID: 29615403.
Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling and BTK inhibition is an effective therapy for MCL patients. Yet, the underlying molecular mechanisms are poorly understood. Using a novel mouse model and phospho-CyTOF analysis, this study shows that transgenic expression of SOX11, a transcription factor over-expressed in the majority of MCL patients, promotes sustained BCR signaling and a disease phenotype reminiscent of human MCL.
New publication from the Stanley Lab - Biswas B, Batista F, Sundaram S, Stanley P. MGAT1 and Complex N-Glycans Regulate ERK Signaling During Spermatogenesis. Sci Rep. 2018 Jan 31;8(1):2022. doi: 10.1038/s41598-018-20465-3.
MGAT1 and complex N-glycans are required for spermatogenesis in mammals. In this paper, we show that conditional deletion of Mgat1 in spermatogonia at 3 days after birth does not give histological defects until 24 days after birth. We performed microarray analysis on germ cells from 22 and 23 day Mgat1 cKO males and identified ERK1/2 signaling as potentially affected. We showed that pERK1/2 is reduced in 22 day male germ cells and that ERK1/2 signaling by the germ cell glycoprotein basigin is reduced in a cell-based model of Mgat1 cKO germ cells.
New publication from the Guo and the Gamble Labs - Hodge DQ, Cui J, Gamble MJ, Guo W. Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition. Sci Rep. 2018 Jan 16;8(1):841. doi: 10.1038/s41598-018-19364-4. PMID: 29339820.
This work identified an unexpected isoform-specific function of the histone variant macroH2A1 in suppressing epithelial-mesenchymal transition, a biological process promoting tumor metastasis and drug resistance.
Two new publications from the Stanley Lab - Wang Y, Wu B, Lu P, Zhang D, Wu B, Varshney S, Del Monte-Nieto G, Zhuang Z, Charafeddine R, Kramer AH, Sibinga NE, Frangogiannis NG, Kitsis RN, Adams RH, Alitalo K, Sharp DJ, Harvey RP, Stanley P, Zhou B.Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1. Nat Commun. 2017 Sep 18;8(1):578. doi: 10.1038/s41467-017-00654-w.
This paper shows that conditional deletion (cKO) of the fucosyltransferase Pofut1 in the endocardium is not as deleterious for Notch signaling as was expected. The milder phenotype in Pofut1 cKO endocardium allowed the discovery of an angiogenic cell population that leads to the development of coronary arteries in mice. This developmental pathway had not previously been observed.
Schneider M, Kumar V, Nordstrøm LU, Feng L, Takeuchi H, Hao H, Luca VC, Garcia KC, Stanley P, Wu P, Haltiwanger RS. Inhibition of Delta-induced Notch signaling using fucose analogs. Nat Chem Biol. 2017 Nov 27. doi: 10.1038/nchembio.2520. [Epub ahead of print]
This paper identifies modified fucose analogs that can be utilized by the fucosyltransferase Pofut1 and transferred to Notch1. Once incorporated, Notch1 with modified fucose exhibits reduced binding of Delta Notch ligands and greatly reduced Notch signaling. The fucose analogs function to inhibit the differentiation of T induced by Delta-induced Notch signaling from bone marrow HSC. These analogs provide an alternative approach to gamma-secretase inhibitors to inhibit Notch signaling in diseases in which ligand-dependent Notch signaling is dysregulated.
From the Schildkraut Lab - Pan X, Drosopoulos WC, Sethi L, Madireddy A, Schildkraut CL, Zhang D. FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres. (2017) Proc Natl Acad Sci U S A.:E5940-E5949. PMID: 28673972.
"Inhibition of telomere length is an important goal in tumor therapy. Some cancer cells use a repair-based human alternative lengthening telomere (ALT) pathway to maintain telomeres. We describe new opportunities to target cancers involving ALT."
From the Fyodorov and Skoultchi Labs - Evgeniya N. Andreyeva, Travis J. Bernardo, Tatyana D. Kolesnikova, Xingwu Lu, Lyubov A. Yarinich, Boris A. Bartholdy, Xiaohan Guo, Olga V. Posukh, Sean Healton, Michael A. Willcockson, Alexey V. Pindyurin, Igor F. Zhimulev, Arthur I. Skoultchi, and Dmitry V. Fyodorov. Regulatory functions and chromatin loading dynamics of linker histone H1 during endoreplication in Drosophila. Genes Dev. 2017; 31: 603-616. PMID: 28404631.
"This study uncovers a direct role for the H1 linker histone in DNA replication, specifically during endoreplication of polytene chromosomes in Drosophila where H1 is critical for formation of under replicated domains. We also discovered that the distribution of H1 changes dramatically during the endocycle S phase. Early in S phase, H1 is heavily deposited in late replicating chromatin and then redistributed as endoreplication proceeds. The results suggest that H1 may play a key role in regulating the locus-specific timing of DNA replication during S phase."
From the Skoultchi Lab - Kokavec J, Zikmund T, Savvulidi F, Kulvait V, Edelmann W, Skoultchi AI, Stopka T. Smarca5 (Snf2h) is required for Proliferation of Hematopoietic Stem Cells Differentiating into Erythroid and Myeloid lineages. Stem Cells. 2017 Mar 9. doi: 10.1002/stem.2604. [Epub ahead of print]. PMID: 28276606
“This study utilizes a new conditional knock-out mouse model for the essential chromatin remodeling ATPase Smarca5 (Snf2h) to explore its role in hematopoiesis. The results show that Smarca5 is required for the proliferation and differentiation of hematopoietic stem and multipotent progenitor cells as well as fully committed erythroid progenitors.”
From the Guo Lab - Wang C., Christin JR., Oktay MH., Guo W.. Lineage-Biased Stem Cells Maintain Estrogen-Receptor-Positive and -Negative Mouse Mammary Luminal Lineages. Cell Reports. 2017 Mar 21;18(12):2825-2835. doi: 10.1016/j.celrep.2017.02.071.
“This study uncovers that estrogen-receptor-positive and -negative luminal cells are two separate lineages that are maintained by distinct lineage-biased stem cells. This finding provides a new framework for studying mammary differentiation and breast cancer etiology.”
From the Stanley Lab - Shogo Sawaguchi, Shweta Varshney, Mitsutaka Ogawa, Yuta Sakaidani, Hirokazu Yagi, Kyosuke Takeshita, Toyoaki Murohara, Koichi Kato, Subha Sundaram, Pamela Stanley, Tetsuya Okajima. O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals. eLife 2017;6:e24419. DOI: http://dx.doi.org/10.7554/eLife.24419.
"It is known that Notch receptors are regulated by O-fucose and O-glucose glycans attached to Ser and Thre in the EGF repeats of their extracellular domain. Our paper shows for the first time that modification by N-acetylglucosamine (O-GlcNAc) also regulates ligand-induced Notch signaling. Importantly, O-GlcNAc regulates signaling by Delta Notch ligands but not by Jagged Notch ligands. Loss of EOGT, the enzyme that transferase O-GlcNAc to Notch, leads to Adams-Oliver Syndrome in humans.”
From the Frenette Lab - Pierce H, Zhang D, Magnon C, Lucas D, Christin JR, Huggins M, Schwartz GJ, Frenette PS. Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay. Cell Stem Cell. 2017 Feb 4. pii: S1934-5909(17)30002-4. doi: 10.1016/j.stem.2017.01.002. [Epub ahead of print].
“This work uncovers a new link between brain and bone marrow where muscarinic receptors expressed in the hypothalamus regulate the HPA axis and alter hematopoietic stem cell migration via hormonal influence.”
From the Frenette Lab - Asada N, Kunisaki Y, Pierce H, Wang Z, Fernandez NF, Birbrair A, Ma'ayan A, Frenette PS. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol. 2017 Feb 20. doi: 10.1038/ncb3475. [Epub ahead of print]
“This work shows that perivascular stromal cells are heterogeneous in their supply of cytokines (CXCL12 and SCF) that regulate hematopoietic stem cell maintenance.”
From the Query Lab - Qing Tang, Susana Rodriguez-Santiago, Jing Wang, Jia Pu, Andrea Yuste, Varun Gupta, Alberto Moldón, Yong-Zhen Xu, and Charles C. Query. SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing. Genes Dev. 2017; 30: 2710-2723.
“In this study, Tang et al. investigated the mechanisms underlying alternate splicing. They show that hsh155 mutant alleles in S. cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal branch site pre-mRNA substrates, thus providing a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease.”
From the Ye Lab - Alvarez M.J., Shen Y., Giorgi F.M., Lachmann A., Ding B.B., Ye B.H., Califano A. Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat Genet. 2016 Aug;48(8):838-47. doi: 10.1038/ng.3593. Epub 2016 Jun 20.
“In this study, a computational algorithm, virtual inference of protein activity by enriched regulon analysis (VIPER), was developed and experimentally validated. We show that VIPER can accurate measure protein activity based on gene expression data, thus accurately predicting aberrant protein functions independent of cancer-associated mutations.”
From the Ye Lab - Mai Y., Yu J.J., Bartholdy B., Xu-Monette Z.Y., Knapp E.E., Yuan F., Chen H., Ding B.B., Yao Z., Das B., Zou Y., Young K.H., Parekh S., Ye B.H. An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL. Blood. 2016 Oct 13. pii: blood-2016-03-705814. [Epub ahead of print].
“In this study, we discovered that a key ingredient in the first-line therapy for diffuse large B-cell lymphomas, doxorubicin, has subtype-specific mechanism of cytotoxicity due to differences in subcellular localization. We also demonstrated that STAT3 promotes resistance to ROS-mediated Dox cytotoxicity by upregulating the expression of SOD2.”
From the Ye Lab - Alvarez M.J., Shen Y., Giorgi F.M., Lachmann A., Ding B.B., Ye B.H., Califano A. Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat Genet. 2016 Aug;48(8):838-47. doi: 10.1038/ng.3593. Epub 2016 Jun 20.
“In this study, a computational algorithm, virtual inference of protein activity by enriched regulon analysis (VIPER), was developed and experimentally validated. We show that VIPER can accurate measure protein activity based on gene expression data, thus accurately predicting aberrant protein functions independent of cancer-associated mutations.”
From the Guo Lab - Zhang Z., Christin J.R,, Wang C., Ge K., Oktay M.H., Guo W.. Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation. Cell Rep. 2016 Sep 20;16(12):3146-56. doi: 10.1016/j.celrep.2016.08.048.
“We have developed an efficient method for generating somatic GEMMs for breast cancer through ex vivo expansion and genome editing of mammary stem cells. Using this platform, We have uncovered the functional roles of several human cancer-associated genes in tumorigenesis and mammary cell fate dysregulation.”.
From the Kielian Lab - Dubé M, Etienne L, Fels M, Kielian M.. Calcium-Dependent Rubella Virus Fusion Occurs in Early Endosomes. J Virol. 2016 Jun 24;90(14):6303-13. doi: 10.1128/JVI.00634-16. Print 2016 Jul 15..
Here we addressed the mechanism of the unusual calcium requirement and the required location of calcium during Rubella virus entry.
From the Fyodorov and Skoultchi Labs - Kavi, H., A. V. Emelyanov, D. V. Fyodorov and A. I. Skoultchi. Independent biological and biochemical functions for individual structural domains of Drosophila linker histone H1. J Biol Chem. 2016 May 18. pii: jbc.M116.730705.
This study reports the first in-depth structure-function analysis of the contributions of individual domains and sub-domains of the H1 linker histone to its multiple functions in chromatin structure and activity in vivo.
From the Skoultchi Lab - Geeven, G., Y. Zhu, B. J. Kim, B. A. Bartholdy, S. M. Yang, T. S. Macfarlan, W. D. Gifford, S. L. Pfaff, M. J. Verstegen, H. Pinto, M. W. Vermunt, M. P. Creyghton, P. J. Wijchers, J. A. Stamatoyannopoulos, A. I. Skoultchi and W. de Laat. Local compartment changes and regulatory landscape alterations in histone H1-depleted cells. Genome Biol 16: 289
• This study uses a combination of genome-wide approaches, including chromosome capture (Hi-C), DNA methylation, histone modification and DNase I hypersensitivity profiling to investigate the impact of reducing cellular levels of H1 linker histone in embryonic stem cells on chromatin folding and function. The results show that H1 plays a major role in the maintenance of topologically associated domains (TADs) and the epigenetic landscape within TADs..
From the Kielian lab - Stiles, KM., Kielian, M. Role of TSPAN9 in Alphavirus Entry and Early Endosomes. 2016. J Virol 90:4289–4297. doi:10.1128/JVI.00018-16.
• TSPAN9 Modulates Early Endosomes To Enhance Fusion of Early-Penetrating Viruses.
From the Steidl lab - Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, Steidl U. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nature Chemical Biology (2015); doi:10.1038/nchembio.1930
• Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are common in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). A novel class of allosteric IDH1 inhibitors is effective against multiple clinically relevant mutants, promoting differentiation of AML blasts and stem-like cells and restoring DNA cytosine methylation patterns.
From the Kielian Lab - Fields, W. Kielian, M. Interactions Involved in pH Protection of the Alphavirus Fusion Protein. Virology 486:173-179. (2015).
• Using site-directed mutagenesis and revertant analysis, we define residues that promote pH protection of the alphavirus fusion protein during its transit through the exocytic pathway.
From the Stanley Lab - Huang HH, Hassinen A, Sundaram S, Spiess AN, Kellokumpu S, Stanley P. GnT1IP-L specifically inhibits MGAT1 in the Golgi via its luminal domain. Elife. 2015 Sep 15;4. doi: 10.7554/eLife.08916.
• We previously identified a testis-specific inhibitor of complex N-glycan synthesis, GnT1IP-L, and now show that it forms heteromers specifically with the glycosyltransferase MGAT1 in the Golgi but not the ER, is expressed in spermatocytes and spermatids, and is absent in men with Sertoli Only Syndrome.