Classification of <scp>CEBPA</scp> mutated acute myeloid leukemia by <scp>GATA2</scp> mutations

Marceau-Renaut, Alice; Guihard, Soizic; Castaigné, Sylvie; Dombret, Hervé; Preudhomme, Claude; Cheok, Meyling

doi:10.1002/ajh.23949

Cited by 12 publications

(9 citation statements)

References 10 publications

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“…The GATA2 mutation landscape in adult de novo AML differs from that in blastic crisis of CML 3 , familial MDS/AML 4 , and pediatric AML 5 . In adult AML, ZF1 mutations predominate, while ZF2 mutations are reported sporadically 10 , 36 , 37 . In concordance with the findings, two-thirds of the 44 distinct GATA2 mutations in our study were located in the ZF1 domain.…”

Section: Discussionmentioning

confidence: 99%

GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia

Tien

Hou

Tsai

et al. 2018

Blood Cancer Journal

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Mutations of the GATA binding protein 2 (GATA2) gene in myeloid malignancies usually cluster in the zinc finger 1 (ZF1) and the ZF2 domains. Mutations in different locations of GATA2 may have distinct impact on clinico-biological features and outcomes in AML patients, but little is known in this aspect. In this study, we explored GATA2 mutations in 693 de novo non-M3 AML patients and identified 44 GATA2 mutations in 43 (6.2%) patients, including 31 in ZF1, 10 in ZF2, and three outside the two domains. Different from GATA2 ZF2 mutations, ZF1 mutations were closely associated with French-American-British (FAB) M1 subtype, CEBPA double mutations (CEBPAdouble-mut), but inversely correlated with FAB M4 subtype, NPM1 mutations, and FLT3-ITD. ZF1-mutated AML patients had a significantly longer overall survival (OS) than GATA2-wild patients and ZF2-mutated patients in total cohort as well as in those with intermediate-risk cytogenetics and normal karyotype. ZF1 mutations also predicted better disease-free survival and a trend of better OS in CEBPAdouble-mut patients. Sequential analysis showed GATA2 mutations could be acquired at relapse. In conclusion, GATA2 ZF1 mutations are associated with distinct clinico-biological features and predict better prognosis, different from ZF2 mutations, in AML patients.

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Section: Discussionmentioning

confidence: 99%

GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia

Tien

Hou

Tsai

et al. 2018

Blood Cancer Journal

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“…It is correct for FLT3-ITD and in particular for NPM1, which are essentially not present among C/EBPα-dm cases [68,78,79]. Recently, the mutation in transcription factor GATA2 was found to have a strong association with C/EBPα-dm mutation [75].…”

Section: Ccaat/enhancer-binding Protein α (C/ebpα) Mutationsmentioning

confidence: 96%

“…Moreover, C-terminal C/EBPα-sm patients may be less distinct from C/EBPα-dm cases than N-terminal C/EBPα-sm patients [68,71,74]. Recent study suggest that homozygous C/EBPα mutations have a similar gene expression signature as C/EBPα-dm and thus may be considered as equivalent [75].…”

Section: Ccaat/enhancer-binding Protein α (C/ebpα) Mutationsmentioning

confidence: 99%

Gene Mutations in Acute Myeloid Leukemia — Incidence, Prognostic Influence, and Association with Other Molecular Markers

Blau¹

2015

Leukemias - Updates and New Insights

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Abstract"cute myeloid leukemia "ML is a clonal disorder affecting pluripotent stem cells and is characterized by ineffective hematopoiesis. Most "ML patients harbor cytogenetic and molecular defects that identify entities with peculiar biologic and clinical data and distinct therapeutic responses. "pproximately %-% of de novo "ML and %-% of secondary "ML patients display chromosomal aberrations.Structural chromosomal rearrangements are the most common cytogenetic abnormalities in de novo "ML, with an incidence of %. Last years, large collaborative studies have demonstrated the importance of cytogenetic aberrations for the prognosis of "ML patients.The large group of patients with cytogenetically normal CN "ML refers to the intermediate risk category. It is known that this group of patients is very heterogeneous with respect to prognosis. The recent large-scale sequencing of "ML genomes is now providing opportunities for patient stratification and personalized approaches to treatments that are based on individual mutation profiles. Genes recurrently mutated in "ML belong to distinct functional groups or pathways. " few recurring gene mutations with prognostic relevance in "ML have been identified and have become incorporated into current prognostication models. For patients with CN "ML, prognosis can be specified by mutational status of the genes NPM , FLT , and CE"P". CN "ML patients with NPM mutation, but no FLT -ITD, or with CE"P" mutation, have a favorable prognosis. In contrast, CN "ML patients with FLT -ITD mutation have a poor prognosis. Recently a new class of mutations affecting genes for DN" methylation and posttranslational histone modification was identified in "ML. These mutations frequently occur in the DN" nucleotide methyltransferase " gene DNMT " and isocitrate dehydrogenase / gene IDH / . Different studies have shown a negative impact of DNMT " mutations on outcomes in patients with "ML. The prognostic effect is known to depend on certain biological factors as well as a combination of cytogenetics and other mutations such as those in FLT and NPM . In contrast, the impact of IDH / mutations on prognosis is not completely understood. It appears that prognosis may depend on specific patient populations and a combination with NPM mutations.Moreover, a growing number of recurrent mutations in additional genes have recently been identified. Increasing evidence suggests that "ML develops throughout the process of branching evolution.

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“…Тем не менее было обнаружено, что пациенты с С-терминальной мутацией C/EBPα-sm меньше отличаются по профилю экспрессии генов от больных с C/EBPα-dm, чем пациенты с N-терминальной мутацией C/EBPα-sm [68,71,74]. Кроме того, известно, что гомозиготные мутации С/EBPα имеют аналогичную C/EBPα-dm экспрессию генов, что позволяет рассма-тривать эти мутации как эквивалентные [75].…”

Section: мутации гена C/ebpαunclassified

“…Этот факт особенно четко прослеживается в отношении мутаций FLT3 и NPM1, которые практически не обнаруживаются у больных с C/EBPα-dm [68,78,79]. Известно, что мутации транскрипционного фактора GATA2 часто сопровождают C/EBPα-dm [75].…”

Section: мутации гена C/ebpαunclassified

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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Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations

Cited by 12 publications

References 10 publications

GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia

GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia

Gene Mutations in Acute Myeloid Leukemia — Incidence, Prognostic Influence, and Association with Other Molecular Markers

Genetic Mutations in Acute Myeloid Leukemia

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