Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations

• Type of Material: Article
• Authors: Zhengqi Wang, Emory University; Kevin Bunting, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Wang and Bunting
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.15236
• Title of Journal or Parent Work: Oncotarget
• Volume: 8
• Issue: 14
• Start Page: 22477
• End Page: 22482
• Grant/Funding Information: We acknowledge our funding sources which include R01DK059380, the Cure Childhood Cancer Foundation, and the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University.
• Keywords: transcriptional heterogeneity; leukemogenesis; PROGENITORS; single-cell gene expression analysis; transcription factor; CLONAL HEMATOPOIESIS; Science & Technology; Cell Biology; Life Sciences & Biomedicine; DIFFERENTIATION; LEUKEMOGENESIS; CELL-PROLIFERATION; LEUKEMIA; STEM-CELLS; Oncology; hematopoiesis
• Research Categories: Health Sciences, General; Health Sciences, Human Development

Abstract

Aging is associated with significant changes in hematopoiesis, including clonal dominance, anemia, myeloid malignancies, and reduced activation of signal transducer and activator of transcription 5 (Stat5). In previous studies, Stat5 deletion surprisingly amplified FLT3/ITD+ myeloid expansion or Myc-driven lymphoid expansion. Here we show that Stat5 deficiency has a strong impact upon transcriptional heterogeneity in single sorted c-Kit+Lin-Sca-1+ (KLS) cells or CD150+CD48- KLS long-term repopulating hematopoietic stem cells (LT-HSC). Single cell polymerase chain reaction (PCR) was performed on selected regulators of multi-lineage hematopoiesis. At least two dominant sub-populations were identified by increased expression of cell cycle regulatory and leukemia-associated genes. Furthermore, in the top expressing quartile of cells, the majority of genes were proportionally overrepresented. In wildtype KLS cells, Stat5 mRNA levels were also strongly correlated with several genes. Since heterogeneity decreases with age or inflammatory or oncogenic stress, these results provide a potential mechanistic linkage to Stat5 expression.