title: The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO.
abstract: AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO-induced MPL.
authors.affiliation: Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Chou
authors.forename: Andrea
authors.initials: A
authors.lastname: Griesinger
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Shan
authors.initials: S
authors.lastname: Lin
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Link
authors.forename: Mahesh
authors.initials: M
authors.lastname: Shrestha
authors.forename: Susumu
authors.initials: S
authors.lastname: Goyama
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mizukawa
authors.forename: Shuhong
authors.initials: S
authors.lastname: Shen
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011289:Preleukemia / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D053628:Receptors, Thrombopoietin; D051020:bcl-X Protein; C082218:MPL protein, human; D013926:Thrombopoietin