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Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 + mouse long-term hematopoietic stem cells.

ABSTRACT: Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single cell transplants and lineage tracing suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). We show that NEO1+ Hoxb5 + LT-HSCs expand with age and respond to myeloablative stress in young mice while NEO1- Hoxb5 + LT-HSCs exhibit no significant change in number. Furthermore, NEO1+ Hoxb5 + LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1- Hoxb5 + LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+ Hoxb5 + LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution while NEO1- Hoxb5 + LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression analysis reveals erythroid and myeloid priming in the NEO1+ fraction and association of quiescence and self-renewal-related transcription factors with NEO1- LT-HSCs. Finally, transplanted NEO1+ Hoxb5 + LT-HSCs rarely generate NEO1- Hoxb5 + LT-HSCs while NEO1- Hoxb5 + LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced NEO1- Hoxb5 + LT-HSCs can hierarchically precede active, myeloid-biased NEO1+ Hoxb5 + LT-HSCs.

SUBMITTER: Gulati GS

PROVIDER: S-EPMC6911217 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ mouse long-term hematopoietic stem cells.

Gulati Gunsagar S GS Zukowska Monika M Noh Joseph J JJ Zhang Allison A Wesche Daniel J DJ Sinha Rahul R George Benson M BM Weissman Irving L IL Szade Krzysztof K

Proceedings of the National Academy of Sciences of the United States of America 20191121 50

Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single cell transplants and lineage tracing suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). We show that NEO1+<i ...[more]

PMID: 31754028

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Project description:BackgroundCurrently, cytogenetic and genetic markers are the most important for risk stratification and treatment of patients with acute myeloid leukemia (AML). Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. Therefore, the identification of new AML biomarkers is useful in the prognosis and monitoring of AML and contributes to a better understanding of the molecular basis of the disease. Homeobox (HOX) genes are transcription factors that lead to cell differentiation blockade and malignant self-renewal. However, the roles of HOX genes in AML are still not fully understood and need further exploration, which may provide new strategies for the prognosis and monitoring of AML.MethodsWe analyzed the RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA), VIZOME, GSE13159, and GSE9476 cohorts. Analyses were performed with GraphPad 7, the R language, and several online databases. We applied quantitative polymerase chain reaction, Western Blotting, CCK8 cell proliferation assays, and flow cytometry to verify the conclusions of the bioinformatics analysis.ResultsWe identified HOXB5 as the only gene among the HOX family that was not only elevated in AML but also a significant prognostic marker in AML patients. HOXB5 was highly expressed in AML patients with NPM1, FLT3, or DNMT3A mutations and was expressed at the highest level in patients with NPM1-FLT3-DNMT3A triple-mutant AML. Gene Ontology analysis and gene set enrichment analysis revealed that HOXB5 showed a negative correlation with the myeloid cell differentiation signature and that the tumor necrosis factor/nuclear factor κB signaling pathway was involved in the molecular mechanism. Moreover, we performed in silico protein-protein interaction analysis and 450K TCGA DNA methylation data analysis and found that HOXB5 interacted with two HOX genes (HOXA7 and HOXB4) that were commonly regulated by DNA methylation levels.ConclusionHOXB5 is associated with the malignant development of AML and may be a treatment target and biomarker for AML prognosis prediction.

Dataset Information

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5 + mouse long-term hematopoietic stem cells.

Publications

Neogenin-1 distinguishes between myeloid-biased and balanced <i>Hoxb5</i><sup>+</sup> mouse long-term hematopoietic stem cells.

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