PUBLICATION

Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish

Authors
Lim, K.H., Chang, Y.C., Chiang, Y.H., Lin, H.C., Chang, C.Y., Lin, C.S., Huang, L., Wang, W.T., Gon-Shen Chen, C., Chou, W.C., Kuo, Y.Y.
ID
ZDB-PUB-161008-4
Date
2016
Source
Blood cancer journal   6: e481 (Journal)
Registered Authors
Chang, Chi-Yao, Huang, Ling-Chuan
Keywords
none
MeSH Terms
  • Gene Expression Regulation, Neoplastic
  • Janus Kinase 2/genetics*
  • Thrombocythemia, Essential/drug therapy
  • Thrombocythemia, Essential/genetics*
  • Thrombocythemia, Essential/pathology
  • Thrombocytosis/drug therapy
  • Thrombocytosis/genetics*
  • Thrombocytosis/pathology
  • Calreticulin/genetics*
  • Myeloproliferative Disorders/drug therapy
  • Myeloproliferative Disorders/genetics*
  • Myeloproliferative Disorders/pathology
  • Primary Myelofibrosis/drug therapy
  • Primary Myelofibrosis/genetics*
  • Primary Myelofibrosis/pathology
  • Carcinogenesis/drug effects
  • Carcinogenesis/genetics
  • Humans
  • Signal Transduction/drug effects
  • Signal Transduction/genetics
  • Disease Models, Animal
  • Hematopoiesis
  • Pyrrolidines/pharmacology
  • Receptors, Thrombopoietin/genetics
  • Animals
  • Sulfonamides/pharmacology
  • Mutation
  • Pyrazoles/pharmacology
  • Zebrafish
  • Hematopoietic Stem Cells/metabolism
(all 30)
PubMed
27716741 Full text @ Blood Cancer J
Abstract
CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB + MO1-eporstandard conditionsDay 5
AB + MO1-mplstandard conditionsDay 5
AB + MO3-csf3rstandard conditionsDay 5
1 - 3 of 3
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
la2TgTransgenic Insertion
    y1TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      myeloproliferative neoplasmTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      csf3rMO3-csf3rMRPHLNO
      eporMO1-eporMRPHLNO
      mplMO1-mplMRPHLNO
      1 - 3 of 3
      Show
      Fish
      Fish
      AB + MO1-epor
      AB + MO1-mpl
      AB + MO3-csf3r
      1 - 3 of 3
      Show
      Antibodies
      No data available
      Orthology
      Gene Orthology
      calr
      calr3a
      calr3b
      1 - 3 of 3
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      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
      No data available
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      Citation
      Lim, K.H., Chang, Y.C., Chiang, Y.H., Lin, H.C., Chang, C.Y., Lin, C.S., Huang, L., Wang, W.T., Gon-Shen Chen, C., Chou, W.C., Kuo, Y.Y. (2016) Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish. Blood cancer journal. 6:e481.