Experimental Hematology
Volume 38, Issue 5 , Pages 384-391 , May 2010

F104S c-Mpl responds to a transmembrane domain−binding thrombopoietin receptor agonist: Proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents

  • Norma E. Fox

      Affiliations

    • Drs. Fox and Lim contributed equally to this work.
  • ,
  • Jihyang Lim

      Affiliations

    • Drs. Fox and Lim contributed equally to this work.
  • ,
  • Rose Chen
  • ,
  • Amy E. Geddis

      Affiliations

    • Corresponding Author InformationOffprint requests to: Amy E. Geddis, M.D., Ph.D., Pediatric Hematology-Oncology, University of California, San Diego, 9500 Gilman Drive, Mailcode 0671, La Jolla, CA 92017

Received 30 September 2009 ,Revised 10 February 2010 ,Accepted 16 February 2010.

References 

  1. Ballmaier M, Germeshausen M, Schulze H, et al. c-Mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001;97:139–146
  2. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-Mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A. 1999;96:3132–3136
  3. King S, Germeshausen M, Strauss G, Welte K, Ballmaier M. Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients. Br J Haematol. 2005;131:636–644
  4. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403
  5. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113:2161–2171
  6. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641–648
  7. Dziewanowska ZE, Matsumoto RM, Zhang JK, et al. Single and multiple oral doses of LGD-4665, a small molecule thrombopoietin receptor agonist, increase platelet counts in healthy male subjects. Blood. ASH Annual Meeting Abstracts. 2007; 110:1298(Abstract).
  8. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–4616
  9. Fox NE, Chen R, Hitchcock I, Keates-Baleeiro J, Frangoul H, Geddis AE. Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: functional characterization and a review of the literature. Exp Hematol. 2009;37:495–503
  10. Onishi M, Mui AL, Morikawa Y, et al. Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer. Blood. 1996;88:1399–1406
  11. Drachman JG, Kaushansky K. Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain. Proc Natl Acad Sci U S A. 1997;94:2350–2355
  12. Yang C, Li YC, Kuter DJ. The physiological response of thrombopoietin (c-Mpl ligand) to thrombocytopenia in the rat. Br J Haematol. 1999;105:478–485
  13. Hitchcock IS, Chen MM, King JR, Kaushansky K. YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation. Blood. 2008;112:2222–2231
  14. Syed RS, Reid SW, Li C, et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature. 1998;395:511–516
  15. Middleton SA, Johnson DL, Jin R, et al. Identification of a critical ligand binding determinant of the human erythropoietin receptor. Evidence for common ligand binding motifs in the cytokine receptor family. J Biol Chem. 1996;271:14045–14054
  16. Barbone FP, Middleton SA, Johnson DL, et al. Mutagenesis studies of the human erythropoietin receptor. Establishment of structure-function relationships. J Biol Chem. 1997;272:4985–4992
  17. Germeshausen M, Ballmaier M, Welte K. MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease. Hum Mutat. 2006;27:296–301
  18. Inagaki K, Oda T, Naka Y, Shinkai H, Komatsu N, Iwamura H. Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities. Blood. 2004;104:58–64
  19. Sakai R, Nakamura T, Nishino T, et al. Xanthocillins as thrombopoietin mimetic small molecules. Bioorg Med Chem. 2005;13:6388–6393
  20. Krause S, Schmoldt HU, Wentzel A, Ballmaier M, Friedrich K, Kolmar H. Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists. FEBS J. 2007;274:86–95

PII: S0301-472X(10)00052-4

doi: 10.1016/j.exphem.2010.02.007

Experimental Hematology
Volume 38, Issue 5 , Pages 384-391 , May 2010