@article{Maria-Paz Garcia-Cuellar_Julia Steger_Elisa Füller_Katrin Hetzner_Robert K. Slany_2015, place={Pavia, Italy}, title={Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia}, volume={100}, url={https://haematologica.org/article/view/7436}, DOI={10.3324/haematol.2015.124032}, abstractNote={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 <em>Meis1</em> transcription. These functional interactions translated into <em>in vivo</em> 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 <em>Flt3</em> and <em>Trib2</em> 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 <em>in vitro</em&gt;. Finally, kinetics and severity of disease in transplantation assays indicated that Pbx3/Meis1 dimers are rate-limiting factors for Hoxa9-induced leukemia.}, number={7}, journal={Haematologica}, author={Maria-Paz Garcia-Cuellar and Julia Steger and Elisa Füller and Katrin Hetzner and Robert K. Slany}, year={2015}, month={Jun.}, pages={905-913} }