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@PHDTHESIS{Holl:992265,
      author       = {Holl, Kristin Joana},
      othercontributors = {Antonin, Wolfram and Pradel, Gabriele},
      title        = {{E}ffect of calreticulin and {JAK}2{V}617{F} driver
                      mutations on mitotic progression in myeloproliferative
                      neoplasms},
      school       = {RWTH Aachen University},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2024-08104, 692077 - 108/20},
      pages        = {1 Online-Ressource : Illustrationen},
      year         = {2024},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, RWTH Aachen University, 2024},
      abstract     = {Myeloproliferative neoplasms (MPN) are diseases of
                      haematopoietic stem cells caused by somatic mutations and
                      clonal expansion of mutated haematopoietic stem and
                      progenitor cells (HSPC). MPNs manifest in various clinical
                      pictures. The most commons are chronic myeloid leukaemia
                      (CML), essential thrombocythemia (ET), polycythaemia vera
                      and primary myelofibrosis (PMF). The present work focuses on
                      Philadelphia-negative MPNs caused by mutations in the Janus
                      Kinase 2 (JAK2) and the calreticulin (CALR).The prevailing
                      working model assumes that the influence of the cellular
                      microenvironment and the acquisition of additional mutations
                      lead to heterogeneous diseases caused by these driver
                      mutations. In the present study, I demonstrate an increased
                      incidence of chromatin segregation defects in haematopoietic
                      cells with stable expression of the mutations CALRdel52 or
                      JAK2V617F. In addition, my studies on murine 32DMPL and
                      human erythroleukemic TF-1MPL cells showed a correlation
                      between the expression of CALRdel52 or JAK2V617F and a
                      defective spindle assembly checkpoint (SAC). This
                      contributes to defective mitosis, which can lead to
                      aneuploidy and tumorigenesis. Overall, this promotes
                      defective mitosis. Further analysis showed that when
                      CALRdel52 or JAK2V617F is expressed, there is a correlation
                      between a defective SAC and an imbalance in the recruitment
                      of SAC factors to mitotic kinetochores. I observed a
                      premature degradation of Cyclin B1 during mitosis in 32DMPL
                      cells with CALRdel52 or JAK2V617F mutations, which is
                      associated with a weakening of the SAC. My analysis results
                      on the duration of mitosis in non-haematopoietic cells
                      support the hypothesis and shows the importance of a
                      defective SAC for non-error-free mitosis. In summary, my
                      research results showed that CALRdel52 or JAK2V617F MPN
                      driver mutations alter mitotic regulation potentially
                      impacting karyotype stability, which could be an important
                      factor for the pathogenesis of MPN.},
      cin          = {513000-4 ; 925510 / 164020 / 160000},
      ddc          = {570},
      cid          = {$I:(DE-82)513000-4_20140620$ / $I:(DE-82)164020_20200124$ /
                      $I:(DE-82)160000_20140620$},
      pnm          = {ERS StUpPD-108/20 - Mitotic progression in hematopoietic
                      malignancies (StUpPD-108/20) / ERS Start-Up (EXS) - Start-Up
                      for Juniorprofessor and Postdocs (EXS-SU) / Excellence
                      Strategy},
      pid          = {G:(ERS)StUpPD-108/20 / G:(DE-82)EXS-SU / G:(DE-82)EXS},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2024-08104},
      url          = {https://publications.rwth-aachen.de/record/992265},
}