title: STAT5 N-domain deleted isoforms are naturally occurring hypomorphs partially rescued in hematopoiesis by transgenic Bcl-2 expression.
abstract: Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of normal and leukemic lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and JAKs. Truncation of STAT5 can be mediated through alternative translation initiation from an internal start codon giving rise to N-terminally deleted isoforms. To determine whether these isoforms could be detected naturally in normal murine tissues, Western blot analyses were performed on heart, lung, brain, spleen, liver, and kidney. Relative expression of full-length to truncated STAT5 was variable among tissues. Since we have previously demonstrated that STAT5abΔN lacks the ability to effectively upregulate pro-survival signals and bcl-2 expression, we used a transgenic mouse approach to next determine whether constitutive expression of human Bcl-2 in STAT5ab(ΔN/ΔN) mouse hematopoietic cells could restore normal hematopoiesis. Transgenic H2K-Bcl-2 expression in hypomorphic STAT5ab(ΔN/ΔN) mice largely rescued peripheral B and T lymphocyte numbers whereas multilineage donor contribution was only rescued to levels about 10% of normal. At the hematopoietic stem cell level, direct competitive repopulation with H2K-Bcl-2/STAT5ab(ΔN/ΔN) against STAT5ab(ΔN/ΔN) competitor showed a corrective effect of Bcl-2 expression whether the STAT5ab(ΔN/ΔN) genotype was competed as the donor or as the host versus H2K-Bcl-2/STAT5ab(ΔN/ΔN) genotype bone marrow cells. Therefore, STAT5abΔN isoforms are heterogeneously expressed and lack key functional activities that can be partially rescued by adding back Bcl-2.
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA.
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Case Western Reserve University Cleveland, OH, USA.
authors.forename: Geqiang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine Atlanta, GA, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
keywords: Bcl-2; Cytokine signaling; JAK/STAT; apoptosis; hematopoiesis