MPL mutations in myeloproliferative disorders

analysis of the PT-1 cohort

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

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Activating mutations of MPL exon 10 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 demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin and higher platelet levels at diagnosis, higher serum erythropoietin levels, endogenous megakaryocytic but not erythroid colony growth, and reduced bone marrow erythroid and overall cellularity. Compared with V617F(-) patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.
Original languageEnglish
JournalBlood
Volume112
Issue number1
Pages (from-to)141-149
Number of pages8
ISSN0006-4971
DOIs
Publication statusPublished - 1. Jul 2008

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Mutation
Alleles
Complementary DNA
Polymerase Chain Reaction
DNA
Growth
Serum

Cite this

Beer, P. A., Campbell, P. J., Scott, L. M., Bench, A. J., Erber, W. N., Bareford, D., ... Green, A. R. (2008). MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood, 112(1), 141-149. https://doi.org/10.1182/blood-2008-01-131664
Beer, Philip A. ; Campbell, Peter J. ; Scott, Linda M. ; Bench, Anthony J. ; Erber, Wendy N. ; Bareford, David ; Wilkins, Bridget S ; Reilly, John T. ; Hasselbalch, Hans C. ; Bowman, Richard ; Wheatley, Keith ; Buck, Georgina ; Harrison, Claire N. ; Green, Anthony R. / MPL mutations in myeloproliferative disorders : analysis of the PT-1 cohort. In: Blood. 2008 ; Vol. 112, No. 1. pp. 141-149.
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abstract = "Activating mutations of MPL exon 10 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 demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5{\%} of JAK2 V617F(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin and higher platelet levels at diagnosis, higher serum erythropoietin levels, endogenous megakaryocytic but not erythroid colony growth, and reduced bone marrow erythroid and overall cellularity. Compared with V617F(-) patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.",
author = "Beer, {Philip A.} and Campbell, {Peter J.} and Scott, {Linda M.} and Bench, {Anthony J.} and Erber, {Wendy N.} and David Bareford and Wilkins, {Bridget S} and Reilly, {John T.} and Hasselbalch, {Hans C.} and Richard Bowman and Keith Wheatley and Georgina Buck and Harrison, {Claire N.} and Green, {Anthony R.}",
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Beer, PA, Campbell, PJ, Scott, LM, Bench, AJ, Erber, WN, Bareford, D, Wilkins, BS, Reilly, JT, Hasselbalch, HC, Bowman, R, Wheatley, K, Buck, G, Harrison, CN & Green, AR 2008, 'MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort', Blood, vol. 112, no. 1, pp. 141-149. https://doi.org/10.1182/blood-2008-01-131664

MPL mutations in myeloproliferative disorders : analysis of the PT-1 cohort. / Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.; Bench, Anthony J.; Erber, Wendy N.; Bareford, David; Wilkins, Bridget S; Reilly, John T.; Hasselbalch, Hans C.; Bowman, Richard; Wheatley, Keith; Buck, Georgina; Harrison, Claire N.; Green, Anthony R.

In: Blood, Vol. 112, No. 1, 01.07.2008, p. 141-149.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - MPL mutations in myeloproliferative disorders

T2 - analysis of the PT-1 cohort

AU - Beer, Philip A.

AU - Campbell, Peter J.

AU - Scott, Linda M.

AU - Bench, Anthony J.

AU - Erber, Wendy N.

AU - Bareford, David

AU - Wilkins, Bridget S

AU - Reilly, John T.

AU - Hasselbalch, Hans C.

AU - Bowman, Richard

AU - Wheatley, Keith

AU - Buck, Georgina

AU - Harrison, Claire N.

AU - Green, Anthony R.

PY - 2008/7/1

Y1 - 2008/7/1

N2 - Activating mutations of MPL exon 10 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 demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin and higher platelet levels at diagnosis, higher serum erythropoietin levels, endogenous megakaryocytic but not erythroid colony growth, and reduced bone marrow erythroid and overall cellularity. Compared with V617F(-) patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.

AB - Activating mutations of MPL exon 10 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 demonstrate that MPL mutations outside exon 10 are uncommon in platelet cDNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin and higher platelet levels at diagnosis, higher serum erythropoietin levels, endogenous megakaryocytic but not erythroid colony growth, and reduced bone marrow erythroid and overall cellularity. Compared with V617F(-) patients, those with MPL mutations were older with reduced bone marrow cellularity but could not be identified as a discrete clinicopathologic subgroup. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation or survival.

U2 - 10.1182/blood-2008-01-131664

DO - 10.1182/blood-2008-01-131664

M3 - Journal article

VL - 112

SP - 141

EP - 149

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -

Beer PA, Campbell PJ, Scott LM, Bench AJ, Erber WN, Bareford D et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008 Jul 1;112(1):141-149. https://doi.org/10.1182/blood-2008-01-131664