Controlled stem cell amplification by HOXB4 depends on its unique proline-rich region near the N terminus.
There is high interest in understanding the mechanisms that drive self-renewal of stem cells. HOXB4 is one of the few transcription factors that can amplify long-term repopulating hematopoietic stem cells in a controlled way. Here we show in mice that this characteristic of HOXB4 depends on a proline-rich sequence near the N terminus, which is unique among HOX genes and highly conserved in higher mammals. Deletion of this domain substantially enhanced the oncogenicity of HOXB4, inducing acute leukemia in mice. Conversely, insertion of the domain into Hoxa9 impaired leukemogenicity of this homeobox gene. These results indicate that proline-rich stretches attenuate the potential of stem cell active homeobox genes to acquire oncogenic properties.
Department of Medicine III, Ludwig-Maximilian-University Hospital, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center, Munich, Germany.|Memorial Sloan Kettering Cancer Center, New York, NY.
Monica
M
Cusan
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.
Naidu M
NM
Vegi
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.
Medhanie A
MA
Mulaw
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.
Shiva
S
Bamezai
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.
Lisa M
LM
Kaiser
Sanford-Burnham Medical Research Institute, San Diego, CA.
Aniruddha J
AJ
Deshpande
Department of Medicine III, Ludwig-Maximilian-University Hospital, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center, Munich, Germany.|German Cancer Consortium, Heidelberg, Germany.|German Cancer Research Center, Heidelberg, Germany.
Philipp A
PA
Greif
Institute for Pathology, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
Leticia
L
Quintanilla-Fend
Molecular Hematology and Oncology, Department of Medicine IV, Halle University Hospital, Halle, Germany.
Stefanie
S
Göllner
Molecular Hematology and Oncology, Department of Medicine IV, Halle University Hospital, Halle, Germany.
Carsten
C
Müller-Tidow
The Terry Fox Laboratory, BC Cancer Agency and the Department of Medicine, University of British Columbia, Vancouver, BC, Canada; and.
Keith R
KR
Humphries
Memorial Sloan Kettering Cancer Center, New York, NY.
Scott A
SA
Armstrong
Department of Medicine III, Ludwig-Maximilian-University Hospital, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center, Munich, Germany.
Wolfgang
W
Hiddemann
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.|Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
Michaela
M
Feuring-Buske
Institute for Experimental Cancer Research, Comprehensive Cancer Center, University Hospital Ulm, Ulm, Germany.
Christian
C
Buske
D000208:Acute Disease; D000818:Animals; D002273:Carcinogens; D000066673:Cell Self Renewal; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007938:Leukemia / Q000209:etiology*; D051379:Mice; D011392:Proline; D020539:Sequence Analysis, Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D002273:Carcinogens; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors; D011392:Proline