Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia

Emadi, Ashkan; Faramand, Rawan; Carter-Cooper, Brandon; Tolu, Seda; Ford, Laurie; Lapidus, Rena G.; Wetzler, Meir; Wang, Eunice S.; Etemadi, Arash; Griffiths, Elizabeth A.

doi:10.1002/ajh.23965

Cited by 72 publications

(52 citation statements)

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“…[5][6][7][8] For one publication containing data on both MDS and oligoblastic AML, 5 we obtained primary data from study authors to determine individual treatment responses for AML patients. Logistic regression was used to estimate the association between mutation status and CR attainment both overall and among the subset of patients receiving HMA as part of frontline therapy.…”

Section: 10mentioning

confidence: 99%

“…4 The presence of these mutations has been suggested to have therapeutic implications in small, retrospective series. [5][6][7][8] Using data from two large referral centers together with previously reported data, we sought to investigate the relationship between somatic gene mutations affecting DNA methylation and HMA response in an expanded AML patient cohort. We did not observe a relationship between response to HMAs and IDH1/2 and TET2 mutations.…”

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confidence: 99%

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Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia

et al. 2016

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Section: 10mentioning

confidence: 99%

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Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia

et al. 2016

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“…However, conclusions from this study are limited by the fact that it only included 42 patients, 7 of whom had mutations in IDH1/2, and larger studies have failed to detect this association. 72,73 Thus, while there is evidence of a possible increased response to hypomethylating agents in patients bearing mutations in the DNA hydroxymethylation pathway, this still requires further exploration. Whether this holds true for WT1 mutations has not been established yet, and prospective evaluations of these findings are required.…”

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confidence: 99%

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

Rampal

Figueroa

2016

Haematologica

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IntroductionThe observations that the Wilms tumor 1 (WT1) protein is expressed in the majority of cases of acute myeloid leukemia (AML), and in addition, is mutated in a proportion of AML cases has led to extensive work over the last several decades to determine the mechanistic role of WT1 in AML. The fact that WT1 may be either overexpressed or mutated has given rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. To date, much of the mechanistic work on WT1 has centered on its function as a transcription factor and the role of its many isoforms. However, more recent work stemming from largescale genomic studies in AML has revealed a new role for WT1 in epigenetic regulation. Indeed, work by several groups has demonstrated that WT1 appears to play a role along with TET proteins in mediating 5-hydroxymethylation of cytosines. These novel observations have given rise to an enhanced understanding of the complexity of this protein and its pathogenic role in leukemogenesis. Herein, we seek to review the major concepts and findings with regard to WT1 in oncogenesis and normal hematopoiesis, as well as any therapeutic strategies that may arise from these observations. WT structure and functionThe WT1 gene was initially identified as an inherited predisposition allele in probands with familial Wilms tumor.1,2 Numerous WT1 missense and nonsense mutations have been described in inherited and sporadic Wilms tumors, a pediatric malignancy affecting the kidneys.3,4 WT1 mutations are identified in approximately 20% of Wilms tumors, and are seen in patients with a familial disposition to these tumors. Wilms tumor is also associated with the Denys-Drash syndrome (DDS), encompassing Wilms tumor, congenital nephrotic syndrome, and XY pseudohermaphroditism, which results from point mutations in WT1. 5,6 Mutations in the intron 9 splice site have been identified in patients with Frasier syndrome, a developmental condition that affects kidneys and genitalia. 7 In addition, WT1 has been implicated in a number of other malignancies, including desmoplastic small cell tumor, breast cancer, retinoblastoma, and lung carcinoma. 8,9 In lung cancer, Wt1 has been shown to play a role in murine lung cancer models driven by Kras mutations where deletion or suppression of Wt1 resulted in senescence of primary murine cells expressing Kras, but had no effect on wild type cells. 10 Furthermore, loss of Wt1 led to decreased proliferation and tumor burden in Kras-driven lung carcinoma, © Ferrata Storti Foundation thus implicating Wt1 as a necessary component of Krasdriven oncogenesis. Taken together, these observations indicate that a spectrum of mutations in WT1 can lead to both inherited developmental syndromes and cancer predisposition.The WT1 protein contains an N-terminal transactivation domain and a C-terminus with four zinc-fingers that share DNA binding motifs with EGR1 1 (Figure 1). Four major WT1 isoforms result from differences in alternative splicing. These isoforms arise through...

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“…При НК-ОМЛ мутации генов IDH1/2 обнаружены в 15 % ОМЛ de novo и 20 % вторичных ОМЛ [24,123,130]. Частота выявления возрастает по мере увеличения возраста больных.…”

Section: мутации генов Idh1 и Idh2unclassified

Genetic Mutations in Acute Myeloid Leukemia

Блау¹

2016

Клиническая онкогематология

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Клиника Шарите, Берлинский медицинский университет, ул. Хин-денбургдамм, д. 30, Берлин, Германия, 12200 РЕФЕРАТОстрый миелобластный лейкоз (ОМЛ) -клональное злокачественное заболевание, характеризующееся не-эффективным гемопоэзом. Большинство больных ОМЛ имеют различные цитогенетические и молекулярно-генетические повреждения, которые сочетаются с опре-деленными биологическими и клиническими особенно-стями заболевания. Примерно у 50-60 % больных de novo и у 80-95 % больных вторичными ОМЛ обнаруживаются хромосомные изменения. Следует отметить, что струк-турные цитогенетические аберрации являются наиболее частыми маркерами и встречаются примерно в 40 % слу-чаев ОМЛ de novo. Достаточно большая группа больных с нормальным кариотипом (НК-ОМЛ), формально отно-сящаяся к категории промежуточного риска, является крайне гетерогенной в отношении прогноза течения за-болевания. В действующие прогностические классифика-ции ОМЛ включены сегодня только некоторые мутации, характеризующиеся известным прогностическим зна-чением, в частности NPM1, FLT3 и C/EBPα. Пациенты с NPM1, но без мутаций FLT3-ITD или с мутациями C/EBPα характеризуются благоприятным прогнозом заболева-ния, а с мутацией FLT3-ITD -неблагоприятным. Недавно выявлен новый класс мутаций, при которых повреждают-ся гены, ответственные за эпигенетические процессы ре-гуляции генома, в частности метилирование ДНК или мо-дификацию гистонов. Среди них наиболее изученными к настоящему времени являются мутации в генах DNMT3A, IDH1/2, TET2 и некоторых других. В целом ряде иссле-дований показан неблагоприятный прогностический эф-фект мутации DNMT3A при ОМЛ. Что касается прогно-стического значения IDH1/2, то данный вопрос еще не до конца ясен. На прогноз заболевания влияет ряд биоло-гических факторов, в т. ч. сочетание с цитогенетически-ми аберрациями и другими мутациями, особенно FLT3 и NPM1. Число исследований, посвященных генетическим мутациям при ОМЛ, постоянно растет. Накопленные к настоящему времени знания о генетических изменениях при ОМЛ подтверждают их роль в возникновении и раз-витии заболевания.Ключевые слова: острый миелобластный лейкоз, ОМЛ, кариотип, цитогенетические аберрации, му-тации генов, прогноз. REVIEWS Genetic Mutations in Acute Myeloid Leukemia OV BlauCharite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200 A new class of mutations affecting genes responsible for epigenetic mechanisms of genome regulations, namely for DNA methylation and histone modification, was found recently. Among them, mutations in genes DNMT3A, IDH1/2, TET2 and some others are the most well-studied mutations to date. A number of studies demonstrated an unfavorable prognostic effect of the DNMT3A mutation in AML. The prognostic significance of the IDH1/2 gene is still unclear. The prognosis is affected by a number of biological factors, including those associated with cytogenetic aberrations and other mutations, especially FLT3 and NPM1. The number of studies of genetic mutations in AML keeps growing. The data on genetic aberrations in AML obtained to date ...

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Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia

Cited by 72 publications

References 26 publications

Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia

Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

Genetic Mutations in Acute Myeloid Leukemia

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