DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype

Nangalia, Jyoti; Nice, Francesca; Wedge, David C.; Godfrey, Anna L.; Grinfeld, Jacob; Thakker, Clare; Massie, Charles E.; Baxter, Joanna; Sewell, David; Silber, Yvonne; Campbell, Peter J.; Green, Anthony

doi:10.3324/haematol.2015.129510

Cited by 110 publications

(97 citation statements)

References 15 publications

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“…JAK2 is the most frequently mutated gene in MPNs and JAK2-V617F (JAK2 V617F ) accounts for .95% of mutations of this gene (Kiladjian 2012). When co-occurring with DNMT3A mutations, the order of acquisition of DNMT3A and JAK2 mutations may be relevant in defining different MPN disease phenotypes (Nangalia et al 2015).…”

Section: Dnmt3a Mutations In Myeloproliferative Neoplasms and Myelodymentioning

confidence: 99%

DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

158

108

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DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies. Here, we discuss the biology of DNMT3A and its role in controlling hematopoietic stem cell fate decisions. In addition, we review how mutant DNMT3A may contribute to leukemogenesis and the clinical relevance of DNMT3A mutations in hematologic cancers. DNA methylation is an epigenetic modification involved in key cellular processes such as transcriptional repression, genomic imprinting, and the suppression of repetitive elements. The first suggestion of a link between DNA methylation and cancer was the observation that human cancers tend to display global hypomethylation compared with normal controls (Feinberg and Vogelstein 1983). Subsequently, the field switched attention to focally hypermethylated regions with the hypothesis that epigenetic silencing of tumor suppressor genes through promoter hypermethylation would drive gene silencing, obviating the need for genetic inactivation of these pathways (Jones and Laird 1999). Investigators then began looking for possible genes/pathways responsible for the observed methylation changes.The deposition and maintenance of DNA methyl marks is orchestrated by DNA methyltransferases. In mammals, three genes encoding proteins with DNA methyltransferase activity have been identified: DNMT1, DNMT3A, and DNMT3B (Okano et al. 1998). DNMT3A and DNMT3B proteins are responsible for establishing the patterns of DNA methylation early in embryogenesis through de novo methylation of unmethylated CpG sites , and DNMT1 maintains such patterns throughout cell division by targeting hemimethylated 6 These authors contributed equally to this work.

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Section: Dnmt3a Mutations In Myeloproliferative Neoplasms and Myelodymentioning

confidence: 99%

DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

158

108

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“…63 As compared with TET2-first patients, JAK2-first patients were more likely to present with PV and to have a thrombotic event. More recently, the same group 64 has shown that DNMT3A mutations also may occur early or late in patients with an MPN, and that mutation order influences phenotype: overall, mutations BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6 CLASSICAL MYELOPROLIFERATIVE NEOPLASMS 685…”

Section: Distinguishing Hereditary Disorders Attributable To Germ Linmentioning

confidence: 99%

Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

Rumi

Cazzola

2017

Blood

215

216

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Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.

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“…Usually affecting a minority only of the myeloproliferative clone(s), they are thereby operationally defined as Bsubclonal^mutations for the purposes of this review. Most of these genetic abnormalities occur at the time of diagnosis, either preceding, accompanying, or following the appearance of phenotypic driver mutations [20,21,63], while some, such as mutations of JARID2 and TP53 [64,65], preferentially accumulate at the time of leukemic transformation. The same set of mutated genes occur in patients with myelodysplastic syndromes and acute leukemia; thereby, these mutations are not diagnostically relevant, if not because they point to the existence of a clonal myeloid disorder in patients in which no driver mutations are detected.…”

Section: Subclonal Mutationsmentioning

confidence: 99%

“…However, the mutational landscape of MPN in general, and of PMF in particular, appeared soon to be much more complex than initially though owing to the occurrence, particularly among patients with PMF, of additional mutations targeting genes involved in the epigenetic gene regulations, the spliceosome, or in oncogenes; these mutations are operatively called as Bsubclonal^since they usually occur in hematopoietic cell subclones of variable size, often but not invariably together with one of the phenotypic driver mutations, and may either antedate or follow the acquisition of phenotypic driver mutations [19]. The order by which these mutations appear in the mutational phylogenesis of MPN contributes to the disease phenotype, while the prognostic relevance if any is far from being appreciated [20,21]. Since these mutations are commonly represented also in myelodysplastic syndromes, other myeloid neoplasia, and acute leukemia, they have no specific diagnostic value, while, on the other hand, they contribute remarkably to the prognosis of patients with PMF.…”

Section: Introductionmentioning

confidence: 98%

What Do Molecular Tests Add to Prognostic Stratification in MF: Is It Time to Add These to Our Clinical Practice?

Guglielmelli

Rotunno

Pacilli

et al. 2015

Curr Hematol Malig Rep

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The molecular landscape of patients with myelofibrosis (MF) includes "phenotypic driver" and "subclonal" mutations. The three driver (JAK2, MPL and CALR)-mutated genes currently represent major diagnostic criteria, unlike subclonal mutations that are not specific for the disease and occur in other myeloid neoplasms. Recent data indicate that selected mutations deserve prognostic significance allowing to identify categories of patients with different survival and risk of leukemia. This review focuses on current knowledge regarding genotype-prognostic correlates in MF, however, with the understanding that this is a rapid moving field and no definite recommendations for the clinicians can be done yet.

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DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype

Abstract: haematologica 2015; 100:e442 LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o n

Cited by 110 publications

References 15 publications

DNMT3A in Leukemia

DNMT3A in Leukemia

Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

What Do Molecular Tests Add to Prognostic Stratification in MF: Is It Time to Add These to Our Clinical Practice?

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