Alternative titles; symbols
HGNC Approved Gene Symbol: MPL
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38): 1:43,337,818-43,354,466 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | Amegakaryocytic thrombocytopenia, congenital, 1 | 604498 | Autosomal recessive | 3 |
| Myelofibrosis with myeloid metaplasia, somatic | 254450 | 3 | ||
| Thrombocythemia 2 | 601977 | Autosomal dominant; Somatic mutation | 3 |
The MPL gene encodes the receptor for thrombopoietin (THPO; 600044), a hematopoietic growth factor that regulates the production of multipotent hematopoietic progenitor cells and platelets.
Penciolelli et al. (1987) first identified this protein as a murine retrovirus that causes mouse acute leukemia, and was thus given the name 'myeloproliferative leukemia virus' (MPLV). The phenotype in mice was characterized by rapid proliferation of erythrocytic, granulocytic, and megakaryocytic progenitor cells, resulting in polycythemia, thrombocytosis, and hepatosplenomegaly. MPLV was shown to be a replication-defective, nonsarcomatogenic retrovirus.
Vigon et al. (1992) cloned the human homolog of the v-mpl oncogene and found that it showed striking homology with members of the hematopoietin receptor superfamily. They obtained 2 types of clones, termed MPLP and MPLK, which had the same 5-prime extremity but differed in their 3-prime ends. The 2 clones were predicted to encode 635- and 572-residue proteins, respectively. The resulting deduced polypeptides contained a common extracellular domain with a putative signal sequence and a common transmembrane domain but differed in their cytoplasmic domain. The extracellular domain of MPL contains the consensus sequences described for members of the hematopoietin receptor superfamily which include IL5R (147851), IL3RA (308385), IL4R (147781), IL7R (146661), IL2RB (146710), erythropoietin receptor (EPOR; 133171), IL6R (147880), GMCSF receptor (CSF2R; 306250), and CSF3R (138971). It also shows similarities to the growth hormone receptor (GHR; 600946) and the prolactin receptor (PRLR; 176761). Northern blot analysis of a human erythroleukemia cell line identified 2 MPL mRNA transcripts: a major 3.7-kb (MPLP) transcript and a minor 2.8-kb (MPLK) transcript.
Mignotte et al. (1994) described 3 types of mRNA encoding different MPL proteins generated by alternative splicing: the major species contains all 12 exons, whereas mRNAs encoding a protein with a smaller cytoplasmic domain are produced by termination of the transcript within intron 10, and mRNAs encoding a putative soluble form of the MPL protein lack exons 9 and 10. The promoter region is GC-rich and contains putative binding sites for proteins of the ETS and GATA families.
Mignotte et al. (1994) demonstrated that the MPL gene contains 12 exons distributed over 17 kb of DNA. Each of the 2 'cytokine receptor domains' of MPL is encoded by a set of 4 exons, the transmembrane by a single exon, and the cytoplasmic domain by 2 exons.
By means of in situ hybridization, Le Coniat et al. (1989) mapped the human MPL gene to chromosome 1p34.
The mechanism by which TPO activates the TPO receptor appears to be similar to that of other hematopoietic cytokines that bind and induce receptor homodimerization. Cwirla et al. (1997) identified 2 families of small peptides that bound to human TPOR and competed with the binding of the natural ligand TPO. The sequences of these peptides were not found in the primary sequence of TPO. Further specific screening identified a 14-amino acid peptide with high affinity that stimulated the proliferation of a TPO-responsive cell line. A dimer derived from this peptide stimulated the in vitro proliferation and maturation of megakaryocytes from human bone marrow cells and promoted an increase in platelet count when administered to normal mice. The findings could aid in the development of a recombinant human TPO used for the treatment of thrombocytopenia resulting from chemotherapy and bone marrow transplantation.
Moliterno et al. (1998) found that MPL was markedly reduced or absent in platelets of all 34 patients with polycythemia vera (PV; 263300) and in 13 of 14 patients with idiopathic myelofibrosis (254450). This abnormality appeared to distinguish polycythemia vera from other forms of erythrocytosis.
Akashi et al. (2000) identified a common myeloid progenitor cell that gives rise to all myeloid lineages. The myeloid progenitor did not express IL7R, but did express MPL, whereas the common lymphoid progenitor expressed IL7R but not MPL. Further differentiation of the common myeloid progenitor into the granulocyte/monocyte progenitor versus the megakaryocyte/erythrocyte progenitor was found to be dependent upon expression of the erythropoietin receptor. The commitment of the common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages was proposed to be a mutually exclusive event.
Congenital Amegakaryocytic Thrombocytopenia 1
The considerable similarities between human congenital amegakaryocytic thrombocytopenia (CAMT1; 604498) and murine mpl deficiency prompted Ihara et al. (1999) to analyze the MPL gene in a patient with CAMT. DNA studies detected compound heterozygosity for 2 mutations in the gene (159530.0001; 159530.0002), both of which were predicted to result in a prematurely terminated MPL protein, which, if translated, would lack all intracellular domains essential for signal transduction. The parents were heterozygous for the mutations.
In 8 CAMT patients, Ballmaier et al. (2001) identified homozygous or compound heterozygous mutations in the MPL gene (see, e.g., 159530.0005; 159530.0008). Five patients had complete loss of MPL function, and 3 had missense mutations that were predicted to affect the extracellular domain. Four of the patients were of Kurdish origin and had consanguineous parents. Although all patients had high serum TPO levels, platelets and hematopoietic progenitor cells showed no reactivity to TPO, as measured by testing TPO-synergism to adenosine diphosphate in platelet activation or by megakaryocyte colony assays. Flow cytometry revealed absent surface expression of the TPO receptor MPL in all 3 patients analyzed.
Role in Myeloproliferative Disorders
Moliterno et al. (2004) identified a heterozygous SNP in the MPL gene (K39N; 159530.0009), designated 'MPL Baltimore,' in approximately 7% of African Americans. Three African American women referred for evaluation of a chronic myeloproliferative disorder (MPD) were found to be heterozygous for K39N. Further studies showed that African Americans with the K39N polymorphism had a significantly higher platelet count than controls without the polymorphism (p less than 0.001) and reduced platelet protein MPL expression. Expression of MPL cDNA containing the K39N substitution in cell lines was associated with incomplete processing and a reduction in MPL protein. Moliterno et al. (2004) concluded that K39N represents a functional MPL polymorphism and is associated with altered protein expression of the thrombopoietin receptor and a clinical phenotype of thrombocytosis (THCYT2; 601977). Individuals who were homozygous for K39N exhibited severe thrombocytosis when compared with appropriate controls. Moliterno et al. (2004) noted that impaired MPL function in the setting of thrombocytosis is counterintuitive, given the phenotype of marked thrombocytopenia in individuals with loss-of-function MPL mutations, but the authors suggested that MPL may also have a negative regulatory role. The K39N substitution was restricted to African Americans.
In affected members of a Japanese family with autosomal dominant essential thrombocythemia, Ding et al. (2004) identified a heterozygous activating germline mutation in the MPL gene (159530.0010).
Pikman et al. (2006) and Pardanani et al. (2006) independently identified gain-of-function somatic mutations in codon 515 of the MPL gene (W515L, 159530.0011; W515K, 159530.0012) in patients with myelofibrosis with myeloid metaplasia (see 254450) and/or essential thrombocythemia.
Gurney et al. (1994) found that Mpl-null mice had an 85% decrease in the number of platelets and megakaryocytes but had normal amounts of other hematopoietic cell types. These mice also had increased concentrations of circulating TPO. These results showed that MPL specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO.
Kimura et al. (1998) found that mice lacking Mpl have hematopoietic stem cell deficiencies that are not limited to the megakaryocytic lineage. Their findings imply that TPO, signaling through MPL, plays a vital physiologic role in the regulation of hematopoietic stem cell production and function.
Carpinelli et al. (2004) performed a suppressor screen in Mpl-null mice using N-ethyl-N-nitrosourea (ENU) mutagenesis. They showed that mutations in the Myb gene (189990) caused a myeloproliferative syndrome and supraphysiologic expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling.
In a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498), Ihara et al. (1999) identified compound heterozygosity for 2 mutations in the MPL gene: a 556C-T transition in exon 4 resulting in a gln186-to-ter (Q186X) substitution, and a 1-bp deletion in exon 10 (1499delT; 159530.0002) resulting in a frameshift and premature stop codon.
For discussion of the 1-bp deletion in the MPL gene (1499delT) that was found in compound heterozygous state in a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498) by Ihara et al. (1999), see 159530.0001.
In a 2-year-old Italian boy with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498), Tonelli et al. (2000) identified compound heterozygous mutations in the MPL gene. One allele carried a 769C-T transition in exon 5, resulting in an arg257-to-cys (R257C) substitution in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The other allele carried a 1904C-T transition in exon 12, resulting in a pro635-to-leu (P635L; 159530.0004) substitution in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. TPO plasma levels were greatly increased in the patient. The same patient appears to have been reported by van den Oudenrijn et al. (2000).
Variant Function
By in vitro cellular studies in K562 human leukemia cells, Tijssen et al. (2008) demonstrated that the R257C mutant was expressed at the cell surface but resulted in significantly impaired TPO signal transduction.
For discussion of the pro635-to-leu (P635L) mutation in the MPL gene that was found in compound heterozygous state in a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498) by Tonelli et al. (2000), see 159530.0003.
Variant Function
By in vitro cellular studies in K562 human leukemia cells, Tijssen et al. (2008) demonstrated that the P635L mutant was not properly expressed at the cell surface and resulted in significantly impaired TPO signal transduction.
In a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498), van den Oudenrijn et al. (2000) identified compound heterozygosity for 2 mutations in the MPL gene: a 305G-C mutation in exon 3, resulting in an arg102-to-pro (R102P) substitution, and a 1473G-A mutation in exon 10 resulting in a trp491-to-ter (W491X; 159530.0006) substitution. The R102P substitution occurs in the extracellular part of the protein. The patient had low platelet counts from birth onwards, but relatively late development of anemia and leukopenia, consistent with the milder type II phenotype.
Variant Function
By in vitro cellular studies in K562 human leukemia cells, Tijssen et al. (2008) demonstrated that the R102P mutant was expressed at the cell surface but resulted in impaired TPO signal transduction.
For discussion of the trp491-to-ter (W491X) mutation in the MPL gene that was found in compound heterozygous state in a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498) by van den Oudenrijn et al. (2000), see 159530.0005.
In a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498), van den Oudenrijn et al. (2000) found homozygosity for a G-to-T transversion in the last base of intron 10 of the MPL gene, resulting in loss of the splice site 5-prime of exon 11.
In a patient with congenital amegakaryocytic thrombocytopenia (CAMT1; 604498), Ballmaier et al. (2001) found compound heterozygosity for 2 mutations in the MPL gene: an 823C-A transversion in exon 5 resulting in a pro275-to-thr (P275T) substitution, and R102P (159530.0005).
Moliterno et al. (2004) found that approximately 7% of African Americans are heterozygous for a single nucleotide substitution in the MPL gene, 1238G-T, which results in a lys39-to-asn substitution (K39N). African Americans with the K39N polymorphism, which the authors designated MPL Baltimore, had a significantly higher platelet count than controls without the polymorphism (p less than 0.001) and reduced platelet protein MPL expression. Moliterno et al. (2004) concluded that K39N represents a functional MPL polymorphism and is associated with altered protein expression of the thrombopoietin receptor and a clinical phenotype of thrombocytosis (601977). Individuals who were homozygous for K39N exhibited severe thrombocytosis when compared with appropriate controls. Moliterno et al. (2004) noted that impaired MPL function in the setting of thrombocytosis is counterintuitive, given the phenotype of marked thrombocytopenia in individuals with loss-of-function MPL mutations, but the authors suggested that MPL may also have a negative regulatory role.
In affected members of a Japanese family with autosomal dominant thrombocythemia-2 (THCYT2; 601977), Ding et al. (2004) identified a heterozygous 1073G-A transition in exon 10 of the MPL gene, resulting in a ser505-to-asn (S505N) substitution. Cellular studies showed that mutant cells had increased cytokine-independent survival and constitutively phosphorylated Mek1/2 (see, e.g., 176872), suggesting that S505N is an activating mutation.
Variant Function
Ding et al. (2009) found that, due to the strong polarity of asparagine, the S505N substitution induced autonomous dimerization of mutant MPL, permitting signal activation in the absence of ligand.
Pikman et al. (2006) identified a somatic 1544G-T transversion in the MPL gene, resulting in a trp515-to-leu (W515L) substitution, in 4 (9%) of 45 patients with myelofibrosis with myeloid metaplasia (see 254450). Two of the patients also had leukocytosis and thrombocytosis at the time of disease presentation. Functional expression studies showed that this was an activating mutation conferring cytokine-independent growth and hypersensitivity to THPO in cell culture. The W515L mutant protein resulted in constitutive phosphorylation of downstream signaling molecules, including JAK2 (147796), STAT3 (102582), and ERK (600997). Expression of W515L in murine bone marrow resulted in a fully penetrant myeloproliferative disorder with thrombocytosis and extramedullary hematopoiesis.
Pardanani et al. (2006) identified a somatic W515L mutation in 9 patients with myelofibrosis with myeloid metaplasia and in 4 with essential thrombocythemia (601977). Six of these patients were also heterozygous for the JAK2 V617F mutation (147796.0001), 2 of whom also carried the MPL W515K mutation (159530.0012)
Pardanani et al. (2006) identified a TG-to-AA mutation in the MPL gene, resulting in a somatic trp515-to-lys (W515K) substitution, in 5 patients with myelofibrosis with myeloid metaplasia (see 254450). Two of the patients also had the W515L mutation (159530.0011) and the JAK2 V617F mutation (147796.0001).
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