• What is MPL?
  • MPL in Myeloproliferative Neoplasms
  • MPL c.1544G>T (W515L)
  • Clinical Trials

MPL

MPL proto-oncogene, thrombopoietin receptor (MPL) is a gene that encodes a protein that resembles members of the hematopoietic receptor superfamily. Missense, nonsense, and silent mutations are observed in cancers such as colorectal cancer, leukemias, lung cancer, and skin cancer.

Related Pathways

Last Updated: April 3, 2018

MPL in Myeloproliferative Neoplasms

The MPL gene is located on chromosome 1p34 and encodes the thrombopoietin receptor. MPL mutations are one of the three most prevalent driver mutations leading to MPN pathophysiology (Barbui et al. 2016), although it is rarely observed in patients diagnosed with PV (COSMIC). Most MPL mutations described in the context of MPNs are missense mutations in exon 10 that lead to a substitution of leucine, lysine, asparagine, or alanine in place of the wild-type tryptophan (Beer et al. 2008; Boyd et al. 2010; Chaligne et al. 2008; Pardanani et al. 2006; Pikman et al. 2006). MPL W515L/K is the most frequently occurring mutation in the context of MPNs (Boyd et al. 2010). In PMF, mutation of MPL is associated with female sex, older age, lower hemoglobin levels, and propensity to developing anemia (Guglielmelli et al. 2007).

MPL W515 mutations are located in the amphipathic juxtamembrane domain of the thrombopoietin receptor; this domain plays an autoinhibitory role to prevent spontaneous activation of the receptor (Pikman et al. 2006; Staerk et al. 2006). Preclinical studies have shown that MPL mutation leads to cytokine-independent growth by G1/S activation in cell cycle control pathway, and constitutive activation of the JAK/STAT, MAP kinase, and PI3K/AKT1/MTOR pathways (Chaligne et al. 2008; Pikman et al. 2006). JAK inhibitors have been shown to ameliorate symptoms caused by MPL mutations in cell lines and mouse models (Chaligne et al. 2008; Koppikar et al. 2010; Pardanani et al. 2007).

Last Updated: April 3, 2018

MPL c.1544G>T (W515L) Mutation in Myeloproliferative Neoplasms

Properties
Location of mutation Juxtamembrane domain (exon 10)
Frequency of MPL mutations in MPNs 0.09% in PV (COSMIC)
3–4% in ET (Pardanani et al. 2006)
6–7% in PMF (Pardanani et al. 2006; Pikman et al. 2006)
Frequency of MPL W515L mutations in MPL-mutated MPNs None Reported in MPL-mutated PV
~50% in MPL-mutated ET (Nunes et al. 2015)
~50% in MPL-mutated PMF (Chaligne et al. 2008; Rumi et al. 2014)
Implications for Targeted Therapeutics
Response to JAK inhibitors Unknown at this time

The MPL W515L mutation results in a substitution at position 515 from a tryptophan (W) residue to a leucine (L) residue in the juxtamembrane domain of the thrombopoietin receptor encoded by the MPL gene. W515 is crucial in maintaining the inactive state of the thrombopoietin receptor in absence of cytokines (Lee et al. 2011). The W515L mutation causes a change in the position of the transmembrane domain resulting in a spatial conformational change in the thrombopoietin receptor structure, which leads to autophosphorylation of JAK2 leading to its constitutive activation (Chaligne et al. 2008; Defour et al. 2013; Lee et al. 2011) Preclinical studies have shown that MPL mutations lead to cytokine-independent growth by G1/S activation in the cell cycle control pathway and constitutive activation of the JAK/STAT, MAP kinase, and PI3K/AKT1/MTOR pathways (Chaligne et al. 2008; Pikman et al. 2006). W515L-mutated cells also displayed hypersensitivity when stimulated by thrombopoietin (Pikman et al. 2006).

Last Updated: April 3, 2018

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