TP53 mutations and polymorphisms in primary myelofibrosis

Raza, Sania S.; Viswanatha, David S.; Frederick, Lori; Lasho, Terra L.; Finke, Christy; Knudson, Ryan A.; Ketterling, Rhett P.; Pardanani, Animesh; Tefferi, Ayalew

doi:10.1002/ajh.22216

Cited by 16 publications

(8 citation statements)

References 27 publications

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“…[3][4][5][6][7][8][9][10][11][12][13][14] In this study, we focused on the A3669G (rs6198) polymorphism of the GR gene in PMF because its frequency has been reported to be increased in PV patients, and the variant has been documented to be able to induce an excess proliferative signaling in hematopoietic cells. 15 With a large cohort of patients with WHO-classified PMF, in this study we provide evidence that the A3669G SNP represents a host predisposition factor for PMF.…”

Section: Discussionmentioning

confidence: 99%

“…11 Hernández-Boluda et al documented a strong association with leukemia and primary nonmyeloid cancers of the Gln/Gln genotype in the codon 751 of the DNA repair XPD gene in ET and PV patients. 12 Other polymorphisms were investigated as host-modifying factors in MPNs, such as TP53 exon 4 codon 72 in PMF 13 and MDM2 SNP 309 in members of families with MPN. 14 However, in these cases, the allele frequencies were not different from the general population, and the SNPs did not determine different presenting characteristics or survival or predispose to hereditary diseases.…”

Section: Introductionmentioning

confidence: 99%

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A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Poletto

Rosti

Villani

et al. 2012

Blood

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The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34 ؉ cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P ‫؍‬ .049) and blast transformation (BT)-free survival (76.7 months vs 261 months; P ‫؍‬ .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio ‫؍‬ 3.3; P ‫؍‬ .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT. (Blood. 2012; 120(15):3112-3117)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Poletto

Rosti

Villani

et al. 2012

Blood

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“…[16][17][18][19] Both have been rarely identified in MF [20][21][22] and often occur in the context of abnormal cytogenetics. 23 However, both patients had a diploid karyotype and neither had transformation to AML.…”

Section: Mutations and Response To Ruxolitinib In Mf 791mentioning

confidence: 99%

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Patel¹,

Newberry

Luthra³

et al. 2015

Blood

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134

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“…[55][56][57] Apoptotic signalling is crucial to megakaryocyte polyploidisation and platelet production. Limited studies have identified that apoptotic signalling processes are disrupted in megakaryocytes of the MPNs.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of the intrinsic apoptotic pathway mediates megakaryocytic hyperplasia in myeloproliferative neoplasms

et al. 2016

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AimsMegakaryocyte expansion in myeloproliferative neoplasms (MPNs) is due to uncontrolled proliferation accompanied by dysregulation of proapoptotic and antiapoptotic mechanisms. Here we have investigated the intrinsic and extrinsic apoptotic pathways of megakaryocytes in human MPNs to further define the mechanisms involved.MethodsThe megakaryocytic expression of proapoptotic caspase-8, caspase-9, Diablo, p53 and antiapoptotic survivin proteins was investigated in bone marrow specimens of the MPNs (n=145) and controls (n=15) using immunohistochemistry. The megakaryocyte percentage positivity was assessed by light microscopy and correlated with the MPN entity, JAK2V617F/CALR mutation status and platelet count.ResultsThe proportion of megakaryocytes in the MPNs expressing caspase-8, caspase-9, Diablo, survivin and p53 was significantly greater than controls. A greater proportion of myeloproliferative megakaryocytes expressed survivin relative to its reciprocal inhibitor, Diablo. Differences were seen between myelofibrosis, polycythaemia vera and essential thrombocythaemia for caspase-9 and p53. CALR-mutated cases had greater megakaryocyte p53 positivity compared to those with the JAK2V617F mutation. Proapoptotic caspase-9 expression showed a positive correlation with platelet count, which was most marked in myelofibrosis and CALR-mutated cases.ConclusionsDisruptions targeting the intrinsic apoptotic cascade promote megakaryocyte hyperplasia and thrombocytosis in the MPNs. There is progressive dysfunction of apoptosis as evidenced by the marked reduction in proapoptotic caspase-9 and accumulation of p53 in myelofibrosis. The dysfunction of caspase-9, which is necessary for proplatelet formation, may be the mechanism for the excess thrombocytosis associated with CALR mutations. Survivin seems to be the key protein mediating the megakaryocyte survival signature in the MPNs and is a potential therapeutic target.

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TP53 mutations and polymorphisms in primary myelofibrosis

Cited by 16 publications

References 27 publications

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Dysregulation of the intrinsic apoptotic pathway mediates megakaryocytic hyperplasia in myeloproliferative neoplasms

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