Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning
Jessica L Bridgford, Su Min Lee, Christine MM Lee, Paola Guglielmelli, Elisa Rumi, Daniela Pietra, Stephen Wilcox, Yash Chhabra, Alan F Rubin, Mario Cazzola, Alessandro M Vannucchi, Andrew J Brooks, Matthew E Call, Melissa J Call
Blood | AMER SOC HEMATOLOGY | Published : 2020
The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F- essential thrombocythemia and primary myelofibrosis patients, respectively, have "canonical" MPL exon 10 driver mutations W515L/K/R/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other "noncanonical" MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional ..View full abstract
Awarded by Australian National Health and Medical Research Council (NHMRC)
Awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC)
This work was supported by the Australian National Health and Medical Research Council (NHMRC; project grant 115734, program grant 1054618, and Independent Research Institute Infrastructure Support Scheme [IRIISS] infrastructure support) and Victorian State Government Operational Infrastructure Support (to Walter and Eliza Hall Institute [WEHI]). Research was carried out in part at the Translational Research Institute (Woolloongabba, QLD, Australia), which is supported by a grant from the Australian government. Molecular characterization of patients followed at the University of Florence and the University of Pavia in Italy was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC; 5x1000) call "Metastatic disease: the key unmet need in oncology" to the MYNERVA project (#21267).