title: Myeloid leukemia factor is a conserved regulator of RUNX transcription factor activity involved in hematopoiesis.
abstract: Defining the function of the genes that, like RUNX1, are deregulated in blood cell malignancies represents an important challenge. Myeloid leukemia factors (MLFs) constitute a poorly characterized family of conserved proteins whose founding member, MLF1, has been associated with acute myeloid leukemia in humans. To gain insight into the functions of this family, we investigated the role of the Drosophila MLF homolog during blood cell development. Here we report that mlf controls the homeostasis of the Drosophila hematopoietic system. Notably, mlf participates in a positive feedback loop to fine tune the activity of the RUNX transcription factor Lozenge (LZ) during development of the crystal cells, one of the two main blood cell lineages in Drosophila. At the molecular level, our data in cell cultures and in vivo strongly suggest that MLF controls the number of crystal cells by protecting LZ from degradation. Remarkably, it appears that the human MLF1 protein can substitute for MLF in the crystal cell lineage. In addition, MLF stabilizes the human oncogenic fusion protein RUNX1-ETO and is required for RUNX1-ETO-induced blood cell disorders in a Drosophila model of leukemia. Finally, using the human leukemic blood cell line Kasumi-1, we show that MLF1 depletion impairs RUNX1-ETO accumulation and reduces RUNX1-ETO-dependent proliferation. Thus, we propose that the regulation of RUNX protein levels is a conserved feature of MLF family members that could be critical for normal and pathological blood cell development.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5547, Université de Toulouse, 31062 Toulouse, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bras
authors.forename: Séverine
authors.initials: S
authors.lastname: Martin-Lannerée
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gobert
authors.forename: Benoît
authors.initials: B
authors.lastname: Augé
authors.forename: Osman
authors.initials: O
authors.lastname: Breig
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sanial
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Marc
authors.initials: M
authors.lastname: Haenlin
authors.forename: Anne
authors.initials: A
authors.lastname: Plessis
authors.forename: Lucas
authors.initials: L
authors.lastname: Waltzer
mesh_terms: D000818:Animals; D019070:Cell Lineage; D017124:Conserved Sequence / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D007814:Larva / Q000166:cytology / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010641:Phenotype; D055550:Protein Stability; D059748:Proteolysis; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C468117:Mlf protein, Drosophila; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D014157:Transcription Factors; C099964:lz protein, Drosophila