title: Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders.
abstract: BACKGROUND
  The myeloproliferative disorders are clonal disorders with frequent somatic gain-of-function alterations affecting tyrosine kinases. In these diseases, there is an increase in DNA damage and a risk of progression to acute leukemia. The molecular mechanisms in myeloproliferative disorders that prevent apoptosis induced by damaged DNA are obscure.
  
  
  METHODS
  We searched for abnormalities of the proapoptotic Bcl-x(L) deamidation pathway in primary cells from patients with chronic myeloid leukemia (CML) or polycythemia vera, myeloproliferative disorders associated with the BCR-ABL fusion kinase and the Janus tyrosine kinase 2 (JAK2) V617F mutation, respectively.
  
  
  RESULTS
  The Bcl-x(L) deamidation pathway was inhibited in myeloid cells, but not T cells, in patients with CML or polycythemia vera. DNA damage did not increase levels of the amiloride-sensitive sodium-hydrogen exchanger isoform 1 (NHE-1), intracellular pH, Bcl-x(L) deamidation, and apoptosis. Inhibition of the pathway was reversed by enforced alkalinization or overexpression of NHE-1, leading to a restoration of apoptosis. In patients with CML, the pathway was blocked in CD34+ progenitor cells and mature myeloid cells. Imatinib or JAK2 inhibitors reversed inhibition of the pathway in cells from patients with CML and polycythemia vera, respectively, but not in cells from a patient with resistance to imatinib because of a mutation in the BCR-ABL kinase domain.
  
  
  CONCLUSIONS
  BCR-ABL and mutant JAK2 inhibit the Bcl-x(L) deamidation pathway and the apoptotic response to DNA damage in primary cells from patients with CML or polycythemia vera.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom. rui.zhao@bbsrc.ac.uk
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: George A
authors.initials: GA
authors.lastname: Follows
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Denis R
authors.initials: DR
authors.lastname: Alexander
mesh_terms: D017209:Apoptosis; D027682:Cation Transport Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D003641:Deamination; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D018014:Gene Transfer Techniques; D016313:Genes, abl / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000235:genetics*; D007963:Leukocytes, Mononuclear; D009196:Myeloproliferative Disorders / Q000097:blood / Q000235:genetics; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2