title: Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant toFlt3-ITD mutations.
abstract: TheFLT3Internal Tandem Duplication (FLT3ITD) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show thatFlt3ITDand cooperatingFlt3ITD/Runx1mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3ITDsimultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively. While FLT3ITDcan activate STAT5 signal transduction prior to birth, this signaling does not alter gene expression until hematopoietic progenitors transition from fetal to adult transcriptional states. Cooperative interactions betweenFlt3ITDandRunx1mutations are also blunted in fetal/neonatal progenitors. Fetal/neonatal progenitors may therefore be protected from leukemic transformation because they are not competent to express FLT3ITDtarget genes. Changes in the transcriptional states of developing hematopoietic progenitors may generally shape the mutation spectra of human leukemias.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Shaina N
authors.initials: SN
authors.lastname: Porter
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cluster
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Busken
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Riddhi M
authors.initials: RM
authors.lastname: Patel
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ryoo
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States.|Department of Genetics, Washington University School of Medicine, St. Louis, United States.
authors.forename: Jeffrey A
authors.identifier: 0000-0002-0766-4200
authors.initials: JA
authors.lastname: Magee
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D053686:Fetal Stem Cells / Q000166:cytology / Q000378:metabolism*; D005333:Fetus; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D050799:STAT5 Transcription Factor; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
keywords: Flt3 Internal tandem duplication; acute myeloid leukemia; cancer biology; developmental biology; hematopoietic stem cell; mouse; stem cells