THE MECHANISM OF ONCOGENIC MUTATIONS IN THE JUXTAMEMBRANE AND TRANSMEMBRANE REGION OF IL7RA AND TPOR/MPL

Mutations in the interleukin-7 receptor alpha chain (IL-7Ra), thymic stromal lymphopoietin protein receptor (TSLPR), and thrombopoietin receptor (TPOR/MPL) are common in the transmembrane and juxtamembrane region in leukaemia and myeloproliferative neoplasms. Our recent studies have recently defined the mechanism of how mutations in the IL-7RA that introduce positive charged amino acids at the extracellular transmembrane boundary contribute to enhanced JAK-STAT signalling and T-cell leukaemia (Campos et al., 2019). Our current studies have identified that the position of introduced cysteine and proline residues at the extracellular-transmembrane boundary in the IL7RA define the strength of constitutive signalling. We have also investigated signalling of clinical mutations of the TPOR/MPL in the transmembrane domain and identify that different mutations provide different strengths of signalling to specific pathways. In addition, we have experimentally identified novel mutations within the transmembrane of TPOR/MPL that result in constitutive activation. Together, these studies highly the important of the structure and function of the transmembrane and juxtamembrane sequences of cytokine receptors in activation of signalling pathways. Campos, L.W., Zenatti, P.P., Pissinato, L.G., Rodrigues, G.O.L., Artico, L.L., Guimaraes, T.R., Archangelo, L.F., Martinez, L., Brooks, A.J., and Yunes, J.A. (2019). Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7RA cause receptor hypersensitivity. Blood 133, 1259-1263.