title: Chk2 drives late G1/early S phase arrest of clonal myeloid progenitors expressing the p210 BCR-ABL tyrosine kinase in response to STI571.
abstract: STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.
authors.affiliation: Istituto di Ematologia e Oncologia Medica Lorenzo e Ariosto Seràgnoli, University of Bologna, Medical School, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mazzacurati
authors.forename: Laura
authors.initials: L
authors.lastname: Pattacini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Brusa
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Michela
authors.initials: M
authors.lastname: Benvenuti
authors.forename: Enza
authors.initials: E
authors.lastname: Barbieri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D002460:Cell Line; D064447:Checkpoint Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl; D016193:G1 Phase / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D016196:S Phase / Q000187:drug effects*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004247:DNA; D064447:Checkpoint Kinase 2; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases