Lambert MP, Jiang J, Batra V, Wu C, Tong W: A novel MPL mutation (Y252H) leads to increased susceptibility to thrombopoietin in essential thrombocythemia. At J Hematol. 2012, 87: 532-534. 10.1002/AJH.23138. Known mutations in MPL and JAK2 account for 57% of the PT-1 patients presented here. Comparisons between this group and the remaining 43% without an identified mutation showed no significant difference in the prevalence of splenomegaly, abnormal cytogenetics, myelofibrotic transformation or acute myeloid leukaemia. There were also no differences between the mutation-negative and mutation-positive groups in histological features other than cellularity. Taken together, these results suggest that mutant patients have a myeloproliferative disorder whose molecular basis remains uncertain. Zhao W, Du Y, Ho WT, Fu X, Zhao ZJ: JAK2V617F and p53 mutations coexist in erythroleucemia and megakaryoblastic leukemic cell lines. Exp haematol Oncol. 2012, 1: 15-10.1186/2162-3619-1-15. In this article, we report the existence of 4 mutant MPL alleles in patients with MPD JAK2 V617F−. Despite platelet cDNA analysis, no mutations outside of exon 10 were detected, eliminating the possibility that such mutations could be confined to the megakaryocytic lineage.
Our results are consistent with 2 previous studies and extend them to 2 previous studies with genomic DNA from 14 adults with MPD28 and 9 children with ET,29, who could not identify MPL mutations outside exon 10. Our results show that mutations outside exon 10 MPL are not a common cause of V617F− SD, but do not exclude the existence of such mutations in a small minority of patients. Changes in other MPL sites have recently been reported, although it is not yet clear whether these are acquired mutations or inherited polymorphisms.30 Previous studies have reported on the W515L and W515K alleles in IMF17,19, but only on the W515L allele in ET.17 Here we show the presence of the W515K allele in ET patients and also report 2 different mutations, which can generate a W515K substitution. We also report 2 patients with ET in whom an MPL S505N allele, previously reported as an inherited mutation, 23,31 was detected in granulocytes but absent in oral cells. In addition, in one of the patients, the mutation was present in only a minority of erythroid colonies, and the other patient had a normal platelet count for several years prior to presentation with ET, making somatic mosaicism unlikely. Taken together, these results strongly suggest that the MPL S505N allele may occur as both an inherited and acquired mutation. Mutations in the KIT gene have been reported in patients with sporadic and familial mast cell proliferation. However, the alleles involved are different, with inherited mutations not seen in acquired diseases and vice versa.32-41 We believe this is the first example of a single allele associated with both acquired and inherited forms of MPD. 59. Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, et al. The Asn505 mutation in the c-MPL gene, which causes familial essential thrombocythemia, induces autonomic homodimerization of the c-Mpl protein due to the high polarity of amino acids. Blood (2009) 114(15):3325–8.
doi: 10.1182/blood-2008-04-149047 Serum erythropoietin levels at baseline in patients with MPL mutation were significantly higher than in JAK2 V617F+, but not in patients with JAK2 V617F− (mean vs. mean; P = < 0.001 or P = 0.6). There were no significant differences in iron status between MPL patients and the two control groups, as assessed by mean serum ferritin and erythrocyte cell volume (Table 2). Philip A. Beer, Peter J. Campbell, Linda M. Scott, Anthony J. Bench, Wendy N. Erber, David Bareford, Bridget S.
Wilkins, John T. Reilly, Hans C. Hasselbalch, Richard Bowman, Keith Wheatley, Georgina Buck, Claire N. Harrison, Anthony R. Green; MPL mutations in myeloproliferative diseases: analysis of the PT-1 cohort. Blood, 2008; 112 (1): 141–149. doi: doi.org/10.1182/blood-2008-01-131664 Because of the extremely low mutation rate and the unknown function of some mutations, we divided these mutations into one group. Compared to MPL-W515L/K mutations, MPL-W515A/R mutations occurred significantly less frequently [48, 52, 57]. However, it is conceivable that MPL-W515A/R mutations function via a mechanism similar to MPL-W515L/K mutations, since they are mutations of the same amino acid. MPL-A519T, L510P and A506T mutations are not gain-of-function mutations, and some scientists have hypothesized that these mutations have no relevance to hematological diseases or may be regulators of other genetic events .
Unlike other mutations, MPL-T487A has been observed in a patient with acute megakaryoblastic leukemia (AML) and induces a myeloproliferative disorder in mice by conferring cytokine-independent cell growth capacity . The MPL-Y252H mutation recently detected in ET also shows a growth-promoting effect . However, the function of the mutations MPL-Y591D, W515-P518delinsKT, S204P/F, IVS 11/12 and IVS 10/11 is still unknown [72–74]. Exon 10 MPL activating mutations have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here, we show that MPL mutations outside exon 10 are rare in platelet cDNA and identify 4 different exon 10 mutations in granulocytic DNA from a retrospective cohort of 200 patients with ET or MFI. Allele-specific polymerase chain reaction was then used for genotype 776 samples from ET patients enrolled in PT-1 studies. MPL mutations were identified in 8.5% of patients treated with JAK2-V617F− and in a single V617F+ patient. Patients carrying the W515K allele had a significantly higher allele load than those carrying the W515L allele, suggesting a functional difference between the 2 variants. Compared to patients with TE V617F+, those with MPL mutations had lower haemoglobin levels and higher platelet counts at diagnosis, higher serum erythropoietin levels, growth of endogenous but not erythroid megakaryocytic colonies, and reduced total bone marrow cellularity.