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Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis.

Chi J, Nicolaou KA, Nicolaidou V, Koumas L, Mitsidou A, Pierides C, Manoloukos M, Barbouti K, Melanthiou F, Prokopiou C, Vassiliou GS, Costeas P - Leukemia (2013)

View Article: PubMed Central - PubMed

Affiliation: The Center for the Study of Haematological Malignancies, Nicosia, Cyprus.

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Somatic frameshift mutations in exon 9 of the calreticulin (CALR) gene were recently identified in patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia and myelofibrosis... Calreticulin is a highly conserved endoplasmic reticulum (ER) luminal Ca-binding chaperone protein with a critical role in the process of glycoprotein folding and a number of other cellular functions both inside and outside the ER, and has three domains with different structural and functional properties; a globular N domain, a proline-rich P domain and an acidic C domain... However, until now the diagnosis of MPNs in the absence of JAK2 mutations has relied on specific clinicopathological criteria, and the frequency of CALR mutations in patients presenting with persistent thrombocytosis is unknown... Of 289 samples tested, 189 (65%) carried a JAK2 V617F mutation and 8 (3%) an MPL codon 515 mutation (7 W515L and 1 W515K)... Of the remaining 92 samples, 25 were found to carry a CALR exon 9 indel mutation (Figure 1a)... Also, patients with either JAK2 V617F or CALR exon 9 mutations had significantly higher platelet counts than patients with thrombocytosis and no mutations (Figure 1b)... Each of the 25 CALR mutant samples was found to harbor one of seven different indels; all leading to a +1 frameshift of the open reading frame, including two that have not been previously described... The most common mutation, found in 13 out of the 25 cases, was a 52-bp deletion of nt1172 to nt1223 of the CALR complementary DNA (cDNA; NM_004343.3)... The second most common mutation was a 5-bp insertion (TTGTC) after position nt1127 of the cDNA found in seven cases... In all five samples we were consistently able to detect the mutation after a 1:10 dilution, giving this assay a sensitivity to a mutant allele burden of 5% or less (e.g. Figure 2d)... Altogether, JAK2 V617F, CALR exon 9 indel and MPL codon W515 mutations were found in 77% of the patients referred to our laboratory for the investigation of persistent thrombocytosis.

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JAK2, MPL and CALR mutation frequency in patients with persistent thrombocytosis and associated hematological parameters. (a) Incidence of JAK2 V617F, MPL W515L/K and CALR exon 9 mutations in 289 patients investigated for thrombocytosis. (b) White blood cell (WBC), hemoglobin (Hb), platelet (PLT) and red blood cell (RBC) counts in the four patient groups studied (*P<0.05, **P<0.01, ****P<0.0001 by one-way analysis of variance with Tukey's multiple testing correction).
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fig1: JAK2, MPL and CALR mutation frequency in patients with persistent thrombocytosis and associated hematological parameters. (a) Incidence of JAK2 V617F, MPL W515L/K and CALR exon 9 mutations in 289 patients investigated for thrombocytosis. (b) White blood cell (WBC), hemoglobin (Hb), platelet (PLT) and red blood cell (RBC) counts in the four patient groups studied (*P<0.05, **P<0.01, ****P<0.0001 by one-way analysis of variance with Tukey's multiple testing correction).

Mentions: Of 289 samples tested, 189 (65%) carried a JAK2 V617F mutation and 8 (3%) an MPL codon 515 mutation (7 W515L and 1 W515K). Of the remaining 92 samples, 25 were found to carry a CALR exon 9 indel mutation (Figure 1a). Patients with JAK2 V617F mutations had, on average, higher hemoglobin concentration compared with patients with thrombocytosis and none of the three mutations studied. Also, patients with either JAK2 V617F or CALR exon 9 mutations had significantly higher platelet counts than patients with thrombocytosis and no mutations (Figure 1b).


Calreticulin gene exon 9 frameshift mutations in patients with thrombocytosis.

Chi J, Nicolaou KA, Nicolaidou V, Koumas L, Mitsidou A, Pierides C, Manoloukos M, Barbouti K, Melanthiou F, Prokopiou C, Vassiliou GS, Costeas P - Leukemia (2013)

JAK2, MPL and CALR mutation frequency in patients with persistent thrombocytosis and associated hematological parameters. (a) Incidence of JAK2 V617F, MPL W515L/K and CALR exon 9 mutations in 289 patients investigated for thrombocytosis. (b) White blood cell (WBC), hemoglobin (Hb), platelet (PLT) and red blood cell (RBC) counts in the four patient groups studied (*P<0.05, **P<0.01, ****P<0.0001 by one-way analysis of variance with Tukey's multiple testing correction).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4017256&req=5

fig1: JAK2, MPL and CALR mutation frequency in patients with persistent thrombocytosis and associated hematological parameters. (a) Incidence of JAK2 V617F, MPL W515L/K and CALR exon 9 mutations in 289 patients investigated for thrombocytosis. (b) White blood cell (WBC), hemoglobin (Hb), platelet (PLT) and red blood cell (RBC) counts in the four patient groups studied (*P<0.05, **P<0.01, ****P<0.0001 by one-way analysis of variance with Tukey's multiple testing correction).
Mentions: Of 289 samples tested, 189 (65%) carried a JAK2 V617F mutation and 8 (3%) an MPL codon 515 mutation (7 W515L and 1 W515K). Of the remaining 92 samples, 25 were found to carry a CALR exon 9 indel mutation (Figure 1a). Patients with JAK2 V617F mutations had, on average, higher hemoglobin concentration compared with patients with thrombocytosis and none of the three mutations studied. Also, patients with either JAK2 V617F or CALR exon 9 mutations had significantly higher platelet counts than patients with thrombocytosis and no mutations (Figure 1b).

View Article: PubMed Central - PubMed

Affiliation: The Center for the Study of Haematological Malignancies, Nicosia, Cyprus.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Somatic frameshift mutations in exon 9 of the calreticulin (CALR) gene were recently identified in patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia and myelofibrosis... Calreticulin is a highly conserved endoplasmic reticulum (ER) luminal Ca-binding chaperone protein with a critical role in the process of glycoprotein folding and a number of other cellular functions both inside and outside the ER, and has three domains with different structural and functional properties; a globular N domain, a proline-rich P domain and an acidic C domain... However, until now the diagnosis of MPNs in the absence of JAK2 mutations has relied on specific clinicopathological criteria, and the frequency of CALR mutations in patients presenting with persistent thrombocytosis is unknown... Of 289 samples tested, 189 (65%) carried a JAK2 V617F mutation and 8 (3%) an MPL codon 515 mutation (7 W515L and 1 W515K)... Of the remaining 92 samples, 25 were found to carry a CALR exon 9 indel mutation (Figure 1a)... Also, patients with either JAK2 V617F or CALR exon 9 mutations had significantly higher platelet counts than patients with thrombocytosis and no mutations (Figure 1b)... Each of the 25 CALR mutant samples was found to harbor one of seven different indels; all leading to a +1 frameshift of the open reading frame, including two that have not been previously described... The most common mutation, found in 13 out of the 25 cases, was a 52-bp deletion of nt1172 to nt1223 of the CALR complementary DNA (cDNA; NM_004343.3)... The second most common mutation was a 5-bp insertion (TTGTC) after position nt1127 of the cDNA found in seven cases... In all five samples we were consistently able to detect the mutation after a 1:10 dilution, giving this assay a sensitivity to a mutant allele burden of 5% or less (e.g. Figure 2d)... Altogether, JAK2 V617F, CALR exon 9 indel and MPL codon W515 mutations were found in 77% of the patients referred to our laboratory for the investigation of persistent thrombocytosis.

Show MeSH
Related in: MedlinePlus