Department of Cell Biology

New Publications

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;
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;
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:
"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.


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