Garcia-Cuellar MP, Steger J, Füller E, Hetzner K, Slany R (2015)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2015
Publisher: Ferrata Storti Foundation
Book Volume: 100
Pages Range: 905-913
Journal Issue: 7
DOI: 10.3324/haematol.2015.124032
Hox homeobox transcription factors drive leukemogenesis efficiently only in the presence of Meis or Pbx proteins. Here we show that Pbx3 and Meis1 need to dimerize to support Hox-induced leukemia and we analyze the molecular details of this cooperation. In the absence of Pbx3, Meis1 was highly unstable. As shown by a deletion analysis Meis1 degradation was contingent on a motif coinciding with the Pbx-binding domain. Either deletion of this sequence or binding to Pbx3 prolonged the half-life of Meis1 by preventing its ubiquitination. Meis1 break-down could also be blocked by inhibition of the ubiquitin proteasome system, indicating tight post-transcriptional control. In addition, Meis1 and Pbx3 cooperated genetically as overexpression of Pbx3 induced endogenous Meis1 transcription. These functional interactions translated into in vivo activity. Blocking Meis1/Pbx3 dimerization abrogated the ability to enhance proliferation and colony-forming cell numbers in primary cells transformed by Hoxa9. Furthermore, expression of Meis1 target genes Flt3 and Trib2 was dependent on Pbx3/Meis1 dimerization. This correlated with the requirement of Meis1 to bind Pbx3 in order to form high affinity DNA/Hoxa9/Meis1/Pbx3 complexes in vitro. Finally, kinetics and severity of disease in transplantation assays indicated that Pbx3/Meis1 dimers are rate-limiting factors for Hoxa9-induced leukemia.
APA:
Garcia-Cuellar, M.-P., Steger, J., Füller, E., Hetzner, K., & Slany, R. (2015). Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia. Haematologica, 100(7), 905-913. https://doi.org/10.3324/haematol.2015.124032
MLA:
Garcia-Cuellar, Maria-Paz, et al. "Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia." Haematologica 100.7 (2015): 905-913.
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