Doctoraatsthesis Jinsong Hu

Op 12 januari 2012 behaalde Jinsong Hu (Labo Hematologie – Immunologie, Vrij Universiteit Brussel, o.l.v. Prof. Karin Vanderkerken) zijn doctoraatstitel met het werk ‘Stress-induced resistance in multiple myeloma: the biological and clinical implications for treatment’ (promoter: Prof. Karin Vanderkerken) . Hij onderzocht hoe hypoxie (lagere zuurstofniveaus) in multiple myeloom kan gebruikt worden om een specifieke therapie te ontwikkelen waarbij de medicatie alleen werkzaam is onder die specifieke omstandigheden en geen normale cellen aantast. In parallel heeft hij nagegaan hoe bepaalde eiwitten (Mcl-1) betrokken zijn in de resistentie van bepaalde myeloma cellen aan bortezomib (Velcade). Zijn werk leidde tot 2 originele publicaties in het toonaangevend vaktijdschrift ‘Blood’.

 

Engelstalig Abstract

Multiple myeloma (MM) is a fatal B-cell malignancy characterized by the production of a monoclonal paraprotein, hypercalcemia,increased bone marrow (BM) angiogenesis, destructive bone disease. Over the past decade, progress in the treatment of MM has transformed our therapeutic approaches and improves the outcome of affected patients. However, MM still remains incurable, and has a high rate of relapse and drug resistance.

In this work, we identified two kinds of stresses (one is environmental stress: the hypoxic niche in the BM; the other is proteasome inhibition induced endoplasmic reticulum stress) and their roles in MM biology. Firstly, we discovered that hypoxia is a key feature of the MM BM microenvironment by using murine 5T33MM model. Importantly, we further demonstrated that the hypoxic niche in MM BM could be used as a target for treatment of MM, and successfully introduced hypoxia-activated treatment strategy into leukemia for the first time. Secondly, focusing on the effect of proteasome inhibition (bortezomib) in MM, we demonstrated the mechanism how bortezomib induces Mcl-1expression via endoplasmic reticulum stress signaling. The results provide the molecular basis for better understanding the mechanism of bortezomib-resistance in MM.

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Publicaties:

  • Hu J, Handisides DR, Van Valckenborgh E, De Raeve H, Menu E, Vande Broek I, Liu Q, Sun JD, Van Camp B, Hart CP, Vanderkerken K.Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug.Blood. 2010 Sep 2;116(9):1524-7.
  • Hu J, Dang N, Menu E, De Bruyne E, Xu D, Van Camp B, Van Valckenborgh E, Vanderkerken K. Activation of ATF4 mediates the unwanted Mcl-1 accumulation by proteasome inhibition. Blood. 2011 Nov 29. [Epub ahead of print]

Auteur : Prof. Dr. Karin VanderKerken –  update januari 2012