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.
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
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
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.
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
kinase, and PI3K/AKT1/MTOR pathways (Chaligne et al.
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
Last Updated: April 3, 2018
MPL c.1543_1544delTGinsAA (W515K) Mutation in Myeloproliferative Neoplasms
The MPL W515K mutation results in
a substitution at position 515 from a tryptophan (W) residue to a lysine (K) 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 the absence of cytokines (Lee et al.
2011). The W515K 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.
et al. 2013; Lee
et al. 2011). In vitro studies have shown that MPL activation led to G1/S transition
activation and cytokine-independent growth (Staerk et al.
Last Updated: April 26, 2018
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