title: The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML.
abstract: A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1(-/-) HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Florian H
authors.initials: FH
authors.lastname: Heidel
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Patricia
authors.initials: P
authors.lastname: Arreba-Tutusaus
authors.forename: Zhu
authors.initials: Z
authors.lastname: Wang
authors.forename: Julia
authors.initials: J
authors.lastname: Gaebel
authors.forename: Carsten
authors.initials: C
authors.lastname: Hirt
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Valera
authors.initials: V
authors.lastname: Vasioukhin
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011379:Prognosis
chemical_list: D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C097906:LLGL1 protein, human