The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells.
Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (MycnM), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwe1, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo, which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Bryan
B
King
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Francesco
F
Boccalatte
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.|Department of Medicine, Quinnipiac University Netter School of Medicine, New Hampshire-MED, Hamden, Connecticut, USA.
Kelly
K
Moran-Crusio
Comprehensive Cancer Center Mainfranken and Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
Elmar
E
Wolf
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Jingjing
J
Wang
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Clarisse
C
Kayembe
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.|Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York, USA.
Charalampos
C
Lazaris
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Xiaofeng
X
Yu
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Beatriz
B
Aranda-Orgilles
Department of Pathology and Cell Biology and Pediatrics, Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA.
Anna
A
Lasorella
Department of Pathology, New York University School of Medicine, New York, New York, USA.|Laura and Isaac Perlmutter Cancer Center, New York, New York, USA.
Iannis
I
Aifantis
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics*; D000066673:Cell Self Renewal / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases
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