Characterization of Tfrc-mutant mice with microcytic phenotypes

Slides:

Advertisements

Similar presentations

An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth by Toshihiko Tanno, Peng Zhang,

Advertisements

Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice by Lara Krieg, Oren Milstein, Philippe Krebs, Yu.

by Benjamin J. Frisch, John M. Ashton, Lianping Xing, Michael W

a c b NcoI Endogenous Cbfb NcoI 15,727bp NcoI NcoI BamH1 BamH1

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency by Tayebeh Soheili, Amandine Durand, Fernando.

The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice by Hitendra Singh Chand, Xin.

Role of AP1/NFE2 binding sites in endogenous α-globin gene transcription by Melanie R. Loyd, Yasuhiro Okamoto, Mindy S. Randall, and Paul A. Ney Blood.

The embryonic origins of erythropoiesis in mammals

Platelet depletion by anti-CD41 (αIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering.

by Sang-Hyun Song, AeRi Kim, Tobias Ragoczy, M. A

Experimental Hematology

EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression

Activation of the vitamin D receptor transcription factor stimulates the growth of definitive erythroid progenitors by Jeffrey Barminko, Brad M. Reinholt,

Nonhemolytic antigen loss from red blood cells requires cooperative binding of multiple antibodies recognizing different epitopes by James C. Zimring,

by Chi Wai So, and Michael L. Cleary

Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma

by Natalie J. Foot, Yew Ann Leong, Loretta E. Dorstyn, Hazel E

by Signe Hässler, Chris Ramsey, Mikael C

Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic.

Developmental- and differentiation-specific patterns of human γ- and β-globin promoter DNA methylation by Rodwell Mabaera, Christine A. Richardson, Kristin.

by Hyung-Gyoon Kim, Kyoko Kojima, C. Scott Swindle, Claudiu V

Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS by Ganesan Keerthivasan, Yang Mei,

Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential by Russell C. DeKelver, Ming Yan, Eun-Young Ahn, Wei-Jong.

A knock-in mouse strain facilitates dynamic tracking and enrichment of MEIS1 by Ping Xiang, Wei Wei, Nicole Hofs, Jack Clemans-Gibbon, Tobias Maetzig,

Identification and characterization of 2 types of erythroid progenitors that express GATA-1 at distinct levels by Norio Suzuki, Naruyoshi Suwabe, Osamu.

TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients by Rafael Bejar, Allegra Lord, Kristen Stevenson, Michal.

The exosome complex establishes a barricade to erythroid maturation

Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with β-thalassemia major by Yongliang Huo, Jonathan R. Lockhart,

TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation by Benyue Zhang, Damilola Oyewole-Said,

MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver by Barbara Bonnesen, Cathrine Orskov, Susanne Rasmussen, Peter.

The second transferrin receptor regulates red blood cell production in mice by Antonella Nai, Maria Rosa Lidonnici, Marco Rausa, Giacomo Mandelli, Alessia.

FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant.

Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia by Shahrzad Jalali, Tammy Price-Troska, Jonas Paludo, Jose Villasboas, Hyo-Jin.

by Laura J. Norton, Alister P. W

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models by Paola Rivera-Munoz, Anouchka P. Laurent,

An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth by Toshihiko Tanno, Peng Zhang,

Volume 123, Issue 6, Pages (December 2005)

Dynamic change of transcription pausing through modulating NELF protein stability regulates granulocytic differentiation by Xiuli Liu, Aishwarya A. Gogate,

Role of the Notch Ligand Delta1 in Embryonic and Adult Mouse Epidermis

by Kamira Maharaj, John J

Volume 37, Issue 5, Pages (November 2012)

Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines by Yanyan Zhang, Liang He, Dorothée.

Hematological phenotypes of hema6 mice.

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells by Mia Eriksson, Pablo Peña-Martínez,

MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs by Silvia Maifrede, Esteban Martinez, Margaret Nieborowska-Skorska, Daniela.

by Geling Li, Emily Waite, and Julie Wolfson

Platelet HMGB1 is required for efficient bacterial clearance in intra-abdominal bacterial sepsis in mice by Hui Zhou, Meihong Deng, Yingjie Liu, Chenxuan.

Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS by Takeshi Sugio, Kohta Miyawaki, Koji Kato, Kensuke Sasaki, Kyohei Yamada,

Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells by Xi Jin, Tingting Qin, Meiling Zhao, Nathanael.

Volume 7, Issue 3, Pages (March 2008)

Volume 4, Issue 2, Pages (February 2009)

Volume 14, Issue 2, Pages (February 2001)

by Megan S. Rost, Ilya Shestopalov, Yang Liu, Andy H. Vo, Catherine E

Molecular Therapy - Nucleic Acids

Twist1 regulates embryonic hematopoietic differentiation through binding to Myb and Gata2 promoter regions by Kasem Kulkeaw, Tomoko Inoue, Tadafumi Iino,

Maintaining extraembryonic expression allows generation of mice with severe tissue factor pathway inhibitor deficiency by Michelle M. Castillo, Qiuhui.

Kiran Batta, Magdalena Florkowska, Valerie Kouskoff, Georges Lacaud

Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models by Trisha R. Sippel, Stefan Radtke, Tayla.

Michael S. Kuhns, Mark M. Davis Immunity

by Yue Wei, Hong Zheng, Naran Bao, Shan Jiang, Carlos E

Clonotypic heterogeneity in cutaneous T-cell lymphoma (mycosis fungoides) revealed by comprehensive whole-exome sequencing by Aishwarya Iyer, Dylan Hennessey,

Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways by Sheryl M. Gough, Liat Goldberg,

A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2 by Shadi Khalil, Maja Holy, Stephen Grado, Robert.

A Function of Fas-Associated Death Domain Protein in Cell Cycle Progression Localized to a Single Amino Acid at Its C-Terminal Region Zi Chun Hua, Sue.

Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells by Sherry Thornton, Harini Raghu,

WT macrophage infusion increased iron levels and rescued microcytic anemia of Hmox1 KO mice. WT macrophage infusion increased iron levels and rescued microcytic.

Spontaneous and strong Tfh cell but not Tfr cell development in IL-2 KO mice. Spontaneous and strong Tfh cell but not Tfr cell development in IL-2 KO mice.

Fig. 1 Deficient CD73 and CD39 expressions and extracellular adenosine concentration in BM of OVX animals. Deficient CD73 and CD39 expressions and extracellular.

by Fabian C. Verbij, Nicoletta Sorvillo, Paul H. P

SY-1425 induces maturation in RARA-high AML

Presentation transcript:

Characterization of Tfrc-mutant mice with microcytic phenotypes by Ashlee J. Conway, Fiona C. Brown, Gerhard Rank, Benjamin T. Kile, Craig J. Morton, Stephen M. Jane, and David J. Curtis BloodAdv Volume 2(15):1914-1922 August 14, 2018 © 2018 by The American Society of Hematology

Ashlee J. Conway et al. Blood Adv 2018;2:1914-1922 © 2018 by The American Society of Hematology

Distribution of Tfrc mutations identified in ENU mutagenesis screens. Distribution of Tfrc mutations identified in ENU mutagenesis screens. (A) Amino acid sequence of the mouse (upper) and human (lower) ectopic helical domain of the Tfrc gene. Mutations identified in murine ENU mutagenesis screens are highlighted (red), with their corresponding RBC mutant strain. Known ligand binding positions include Tf binding (yellow), HFE binding (blue), and sites with overlapping Tf/HFE binding (gray). (B) Three-dimensional structure of the murine TfR-Tf complex (PD entry 3S9L) inspected by PyMOL (version 2.0.3). A cluster of Tfrc mutations (RBC5, orange; RBC6, blue; RBC21, red) is highlighted. (C) Closer inspection of the RBC21 mutation and its positioning within the TfR-Tf complex. The R654 amino acid (human equivalent, R651) is shown to have a direct Tf binding role via interactions with Tf amino acids C368 and D356. Other mutation sites (RBC5, RBC6) are suggested to play structural roles within the receptor. Ashlee J. Conway et al. Blood Adv 2018;2:1914-1922 © 2018 by The American Society of Hematology

Phenotype of the RBC21 mouse. Phenotype of the RBC21 mouse. (A) Peripheral blood smears of 7-week-old WT and RBC21 heterozygous (Tfrc+/R654H) mice (original magnification ×400; hematoxylin and eosin stain). Heterozygotes show microcytic red cells with mild pallor. (B) Flow cytometric analysis of CD71 expression levels, performed on live Ter-119+ bone marrow erythroblasts of WT, RBC6 (Tfrc+L645R), and RBC21 (Tfrc+/R654H) mice. (C) Timed pregnancies showing WT, RBC21 homozygous (TfrcR654H/R654H), and RBC6/RB21 double-heterozygous (TfrcL645R/R654H) embryos, dissected at embryonic days 14.5, 16.5, and 18.5. (D) Fetal liver live cell counts performed on WT and RBC21 homozygous (TfrcR654H/R654H) embryos at embryonic day 14.5 (n = 4). (E) Flow cytometric analysis of CD71 expression levels, performed on live Ter-119+ fetal liver cells of WT and RBC21 homozygous (TfrcR654H/R654H) embryos at embryonic day 14.5. (F) Survival curve of irradiated adult mice transplanted with WT or RBC21 homozygous (TfrcR654H/R654H) fetal liver cells, extracted from E14.5 embryos. Median survival of homozygous cohort, 13 days (n = 12). *P < .05. Tx, treatment. Ashlee J. Conway et al. Blood Adv 2018;2:1914-1922 © 2018 by The American Society of Hematology

Analysis of TfR binding and internalization using Amnis flow imaging cytometry. Analysis of TfR binding and internalization using Amnis flow imaging cytometry. (A) CD71/Ter-119 colocalization imaging of erythroblasts obtained from the bone marrow of WT, RBC6 (Tfrc+/L645R), and RBC21 (Tfrc+/R654H) mice. Intensity of CD71/Ter-119 overlap (yellow) generates the median bright detail similarity score. (B) Tf/CD71 colocalization imaging of erythroblasts from the 3 cohorts. Intensity of Tf/CD71 overlap (pale blue) generates the median bright detail similarity score, which is normalized to generate the mean percentage of Tf saturation. (C) Tf/Ter-119 internalization imaging of erythroblasts from each cohort at 0 minutes (before initiation of endocytosis). The mean internalization erode score of Tf uses Ter-119 as the mask. (D) Tf/Ter-119 internalization imaging of erythroblasts from each cohort at 5 minutes postinitiation of endocytosis. All scores represent 2000 Ter-119+ events captured in each cohort. (E) Total time course of Tf uptake, via endocytosis, calculated in Ter-119+ erythroblasts from each cohort. Mean ± (SD) shown in error bars. (F) Quantitative real-time polymerase chain reaction of liver Hamp-1 messenger RNA expression in each cohort. Mean ± (SD) shown (n = 6). *P < .05, **P < .01. MAD, median average deviation. Ashlee J. Conway et al. Blood Adv 2018;2:1914-1922 © 2018 by The American Society of Hematology