title: Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target.
abstract: The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34(+) progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation.
authors.affiliation: 1] Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics, Columbus, OH, USA [2] Blood Center of Wisconsin, Blood Research Institute, Milwaukee, WI, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Harb
authors.forename: P
authors.initials: P
authors.lastname: Neviani
authors.forename: B J
authors.initials: BJ
authors.lastname: Chyla
authors.forename: J J
authors.initials: JJ
authors.lastname: Ellis
authors.forename: G J
authors.initials: GJ
authors.lastname: Ferenchak
authors.forename: J J
authors.initials: JJ
authors.lastname: Oaks
authors.forename: C J
authors.initials: CJ
authors.lastname: Walker
authors.forename: P
authors.initials: P
authors.lastname: Hokland
authors.forename: D C
authors.initials: DC
authors.lastname: Roy
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.forename: C S
authors.initials: CS
authors.lastname: Huettner
authors.forename: D
authors.initials: D
authors.lastname: Perrotti
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011687:Purines / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007211:Indoles; D011687:Purines; D013449:Sulfonamides; D051020:bcl-X Protein; D016044:Fusion Proteins, bcr-abl; C572919:PP242; C528561:navitoclax