Calreticulin Mutations Activate MPL Signaling and Calreticulin Expression Can Modulate MPL Signaling
- Author(s): Brooks, Stefan
- Advisor(s): Fleischman, Angela G
- et al.
Myeloproliferative Neoplasms are a collection of blood cancers in which there is a dysregulation of hematopoiesis leading to an over proliferation of myeloid cells. These are often caused by activating mutations in non-receptor tyrosine kinases. Recently, mutations in the C terminus of calreticulin have been discovered in MPN patients.
Our lab has confirmed that in the presence of the TPO receptor MPL, these mutations constitutively activate the JAK/STAT pathway. Our lab has also discovered that overexpression of wild type calreticulin may suppress MPL signaling leading to impairment of self-renewal in vivo, a reduction in colony formation from sorted LKS cells that overexpress calreticulin and a physical interaction between MPL and calreticulin. Furthermore, our lab has demonstrated that loss of calreticulin leads to an increase in frequency of cell populations in the bone marrow that express MPL including LKS, LKS-SLAM and MEPs, loss of calreticulin leads to an increase of colony formation for LKS cells and discovered the absence of calreticulin in LKS cells leads to a competitive advantage, in vivo, further suggesting that loss of calreticulin leads to enhanced MPL signaling. This dissertation helps to demonstrate a role for calreticulin in hematopoiesis.