title: Ectopic expression of PAX5 promotes maintenance of biphenotypic myeloid progenitors coexpressing myeloid and B-cell lineage-associated genes.
abstract: The transcription factor PAX5 is a critical regulator of B-cell commitment and development. Although normally not expressed in myeloid progenitors, PAX5 has recently been shown to be frequently expressed in myeloid malignancies and to suppress expression of myeloid differentiation genes, compatible with an effect on the differentiation or maintenance of myeloid progenitors. However, previous studies in which PAX5 was ectopically expressed in normal myeloid progenitors in vivo and in vitro provided conflicting results as to the effect of PAX5 on myeloid development. Herein, we demonstrate that on ectopic expression of PAX5 in bone marrow multipotent stem/progenitor cells, cells with a biphenotypic B220(+)GR-1/MAC-1(+) phenotype are produced. These remain cytokine-dependent, but unlike control-transduced cells they sustain long-term generation of myeloid progenitors in vitro and remain capable of myeloid differentiation. Notably, PAX5(+)B220(+)GR-1/MAC-1(+) myeloid progenitors coexpress, at the single-cell level, myeloid genes and otherwise B-cell-specific PAX5 target genes. These findings establish that ectopic expression of PAX5 introduces extensive self-renewal properties in otherwise short-lived myeloid progenitors. Along with the established ectopic expression of PAX5 in acute myeloid leukemia, this motivates a careful investigation of the potential involvement of ectopic PAX5 expression in myeloid and biphenotypic leukemias.
authors.affiliation: Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Klinikgatan 26, 221 84 Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Corinne
authors.initials: C
authors.lastname: Rusterholz
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.forename: Christina T
authors.initials: CT
authors.lastname: Jensen
authors.forename: Karl
authors.initials: K
authors.lastname: Bacos
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D019707:Receptors, Chemokine / Q000096:biosynthesis
chemical_list: C503133:Gr-1 protein, mouse; D016177:Macrophage-1 Antigen; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D019707:Receptors, Chemokine; D017493:Leukocyte Common Antigens