Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations
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...
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| Published in | Oncotarget Vol. 8; no. 14; pp. 22477 - 22482 |
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| Main Authors | , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Impact Journals LLC
04.04.2017
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| 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 wild-type 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. |
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| AbstractList | 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 wild-type 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. 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 wild-type 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. |
| Author | Wang, Zhengqi Bunting, Kevin D |
| AuthorAffiliation | 1 Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28390194$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1038/nature13038 10.1038/nm.3733 10.1182/blood-2008-09-181107 10.1182/blood-2011-06-359232 10.1182/blood-2014-02-555292 10.1056/NEJMoa1408617 10.1182/blood-2007-08-108324 10.1038/nature19348 10.4161/jkst.27159 10.1172/JCI83024 10.1182/blood-2015-03-631747 10.1073/pnas.94.26.14553 10.1016/j.stem.2010.07.016 10.1016/j.cell.2015.11.013 10.1084/jem.20091318 10.1016/j.stem.2010.02.002 10.18632/oncotarget.5009 10.1016/j.stem.2015.08.011 10.1056/NEJMoa1409405 10.1002/hep.23882 |
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| Keywords | single-cell gene expression analysis transcription factor hematopoiesis leukemogenesis transcriptional heterogeneity |
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| SubjectTerms | Animals Cell Lineage - genetics Cells, Cultured Embryo, Mammalian Genetic Heterogeneity Hematopoiesis - genetics Hematopoietic Stem Cells - physiology Mice Mice, Transgenic Research Paper STAT5 Transcription Factor - genetics Transcription, Genetic - genetics |
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| Title | Stat5 deficiency decreases transcriptional heterogeneity and supports emergence of hematopoietic sub-populations |
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