title: Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis.
abstract: Oncogene-mediated transformation of hematopoietic cells has been studied extensively, but little is known about the molecular basis for restriction of oncogenes to certain target cells and differential cellular context-specific requirements for oncogenic transformation between infant and adult leukemias. Understanding cell type-specific interplay of signaling pathways and oncogenes is essential for developing targeted cancer therapies. Here, we address the vexing issue of how developmental restriction is achieved in Down syndrome acute megakaryoblastic leukemia (DS-AMKL), characterized by the triad of fetal origin, mutated GATA1 (GATA1s), and trisomy 21. We demonstrate overactivity of insulin-like growth factor (IGF) signaling in authentic human DS-AMKL and in a DS-AMKL mouse model generated through retroviral insertional mutagenesis. Fetal but not adult megakaryocytic progenitors are dependent on this pathway. GATA1 restricts IGF-mediated activation of the E2F transcription network to coordinate proliferation and differentiation. Failure of a direct GATA1-E2F interaction in mutated GATA1s converges with overactive IGF signaling to promote cellular transformation of DS fetal progenitors, revealing a complex, fetal stage-specific regulatory network. Our study underscores context-dependent requirements during oncogenesis, and explains resistance to transformation of ostensibly similar adult progenitors.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jan-Henning
authors.initials: JH
authors.lastname: Klusmann
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Godinho
authors.forename: Kirsten
authors.initials: K
authors.lastname: Heitmann
authors.forename: Aliaksandra
authors.initials: A
authors.lastname: Maroz
authors.forename: Mia Lee
authors.initials: ML
authors.lastname: Koch
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000503:physiopathology; D050684:E2F Transcription Factors / Q000378:metabolism; D005333:Fetus; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020014:K562 Cells; D007947:Leukemia, Megakaryoblastic, Acute / Q000473:pathology / Q000503:physiopathology*; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D034061:Thrombopoiesis / Q000502:physiology*; D050680:Transcription Factor DP1 / Q000235:genetics
chemical_list: D050684:E2F Transcription Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D013002:Somatomedins; D050680:Transcription Factor DP1; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases