Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning
- Author(s)
- Bridgford, JL; Lee, SM; Lee, CMM; Guglielmelli, P; Rumi, E; Pietra, D; Wilcox, S; Chhabra, Y; Rubin, AF; Cazzola, M; Vannucchi, AM; Brooks, AJ; Call, ME; Call, MJ;
- Journal Title
- Blood
- Abstract
- The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/MPL), 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-negative essential thrombocythemia (ET) and primary myelofibrosis (PMF) 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 'non-canonical' 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 consequences and relevance to disease are unknown. Here we used a deep mutational scanning (DMS) approach to evaluate all possible single-amino-acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba/F3 cells. We identified all currently recognized driver mutations and seven novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.
- Publisher
- ASH
- Research Division(s)
- Structural Biology; Bioinformatics; Advanced Technology And Biology
- PubMed ID
- 31697803
- Publisher's Version
- https://doi.org/10.1182/blood.2019002561
- NHMRC Grants
- NHMRC/1054618,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-14 10:36:56
Last Modified: 2023-06-15 01:53:55