Role of PBX Proteins in Hematopoiesis and Growth Control
Principal Investigator: Michael Cleary
Abstract: Pbx1 is a proto-oncogene that was originally discovered at the site of chromosomal translocations in pediatric acute leukemia. It codes for a TALE class homeodomain transcription factor, which is a component of hetero-oligomeric protein complexes that regulate developmental gene expression. Using genetic approaches, we are investigating the contributions of Pbx1, and the related Pbx2 and Pbx3 proteins, to development and tissue homeostasis. Our studies are beginning to^define molecular pathways that are critically dependent on Pbx functions, most prominent of which are pathways regulated by Hox and orphan homeodomain proteins. In addition, our studies have highlighted cellular populations and processes that are critically dependent on Pbx function. A consistent observation in multiple organ systems is the reduction in proliferating progenitors, however it is unclear whether this is a primary deficiency in progenitor proliferation or a defect in the production of progenitors from tissue-specific stem cells. The resolution of this issue requires an ability to analyze the fates of single phenotypically and functionally defined cells in vivo and in vitro. The hematopoietic compartment is particularly well suited to such analyses given the defined lineal relationships of stem cells and progenitors, and our ability to prospectively isolate distinct progenitor populations. The studies in this application will address the hypothesis that Pbx proteins coordinate cellular processes that underlie the decision of hematopoietic progenitors to self-renew or differentiate. Through four specific aims we will: determine Pbx contributions to HSC self-renewal and multi-lineage differentiation;characterize specific defects in committed progenitors, their proliferation potential, and generation from stem cells;define transcriptional and signaling pathways affected by the absence of Pbx proteins in stem and progenitor cells;and characterize the functional cooperation among Pbx isoforms in hematopoiesis. Given that Pbx1 is a proto-oncogene that is targeted by chromosomal translocations in B cell progenitor and myeloid leukemias, our studies will be particularly relevant for defining Pbx roles in stages of hematopoiesis that serve as the setting for hematologic malignancies initiated by malfunction of Pbx/Hox transcriptional regulatory pathways.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT
- B-cell development fails in the absence of the Pbx1 proto-oncogeneMrinmoy Sanyal
Department of Pathology, Stanford University, School of Medicine, Stanford, CA 94305, USA
Blood 109:4191-9. 2007..Thus, Pbx1 critically functions at a stage between hematopoietic stem cell development and B-cell commitment and, therefore, is one of the earliest-acting transcription factors that regulate de novo B-lineage lymphopoiesis...
- Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescenceFrancesca Ficara
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Cell Stem Cell 2:484-96. 2008..Prospectively isolated, Pbx1-deficient LT-HSCs display altered transcriptional responses to TGF-beta stimulation in vitro, suggesting a possible mechanism through which Pbx1 maintenance of stem cell quiescence may in part be achieved...
- Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart diseaseKryn Stankunas
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Circ Res 103:702-9. 2008..Thus, varied deficiencies in the Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies...
- Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tractChing Pin Chang
Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Development 135:3577-86. 2008..Thus, Pbx1 makes a crucial contribution to distinct regulatory pathways in cardiovascular development...
- Pbx1 restrains myeloid maturation while preserving lymphoid potential in hematopoietic progenitorsFrancesca Ficara
Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy
J Cell Sci 126:3181-91. 2013..These results demonstrate a role for Pbx1 in restraining myeloid maturation while maintaining lymphoid potential to appropriately regulate progenitor reservoirs...
- Essential role for Pbx1 in corneal morphogenesisMark J Murphy
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
Invest Ophthalmol Vis Sci 51:795-803. 2010..This study was performed to elucidate the role of the Pbx1 TALE protein in the corneal epithelium of mice...
- TALE homeodomain proteins regulate site-specific terminal differentiation, LCE genes and epidermal barrierBen Jackson
Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
J Cell Sci 124:1681-90. 2011..We conclude that epidermal barrier genes, such as the LCE multigene cluster, are regulated by TALE homeodomain transcription factors to produce regional epidermal barriers...