GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.
Wang
Zhong
Z
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Iwasaki
Masayuki
M
Ficara
Francesca
F
Lin
Chenwei
C
Matheny
Christina
C
Wong
Stephen H K
SH
Smith
Kevin S
KS
Cleary
Michael L
ML
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000517:prevention & control; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; C084563:Cdx4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D007211:Indoles; C000616391:MEIS1 protein, human; D008301:Maleimides; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; C417521:SB 216763; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C083400:PBX1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D050882:CREB-Binding Protein; D038362:Glycogen Synthase Kinase 3