Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation

Renneville, Aline; Mialou, Valérie; Philippe, N; Kagialis-Girard, Sandrine; Biggio, Valéria; Zabot, MT; Thomas, Xavier; Bertrand, Yves; Preudhomme, Claude

doi:10.1038/leu.2008.294

Cited by 44 publications

(37 citation statements)

References 10 publications

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“…II.5, III.7, IV.2, IV.3) who died of AML but before DNA was collected and who presumably had the Q311P mutation. This is lower than the almost complete penetrance reported in the literature for the N-terminal frameshift mutations, 4,[7][8][9][10] although the sample sizes are limited in these studies.…”

Section: Discussioncontrasting

confidence: 48%

“…Germline mutations in CEBPA are associated with familial AML. 4,[7][8][9][10] To date, the majority of reported variants have been N-terminal frameshift mutations that create a premature stop codon and thus trigger transcription from an alternate start site; this results in the production of a truncated 30-kDa isoform, which lacks a transactivation domain. In addition, a study by Taskesen et al has also identified germline C-terminal mutations associated with AML.…”

Section: Discussionmentioning

confidence: 99%

“…Five additional pedigrees have been identified with similar germline N-terminal frameshift insertions and deletions, leading to the production of the alternate dominant-negative 30-kDa product (Online Supplementary Table S1). [7][8][9][10] These germline mutations have also been frequently associated with somatic C-terminal insertions or deletions. This evidence suggests that the pathogenesis of AML caused by CEBPA may require bi-allelic inactivation of the gene.…”

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confidence: 99%

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Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

et al. 2015

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F amilial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-a (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPa. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-a to bind DNA and reduces transactivation, leading to acute myeloid leukemia.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

et al. 2015

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“…[2][3][4][5][6][7][8][9][10][11][12][13] Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13% 4,8,14 ; among these, 7% to 11% have germline CEBPA mutations. 4,8 The majority of the AML patients have 2 CEBPA mutations with both N-terminal frameshift mutation and C-terminal inframe mutation on different alleles.…”

Section: Aml With Germline Cebpa Mutationmentioning

confidence: 99%

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

Gao

Gong

Chen

2018

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Myeloid neoplasms with familial occurrence have been rarely reported in the past. With the advance of molecular technology and better understanding of the molecular pathogenesis of myeloid neoplasms, investigating the genetic causes of familial acute myeloid leukemia or myelodysplastic syndrome has become feasible in the clinical setting. Recent studies have identified a rapidly expanding list of germline mutations associated with increased risks of developing myeloid neoplasm in the affected families. It is important to recognize these entities, as such a diagnosis may dictate a unique approach in clinical management and surveillance for the patients and carriers. Objective.— To raise the awareness of myeloid neoplasms arising in the setting of familial inheritance among practicing pathologists. Data Sources.— Based on recent literature and the 2016 revision of the World Health Organization classification of hematopoietic neoplasms, we provide an up-to-date review of myeloid neoplasm with germline predisposition. Conclusions.— This short review focuses on the clinical, pathologic, and molecular characterization of myeloid neoplasm with germline predisposition. We emphasize the important features that will help practicing pathologists to recognize these newly described entities.

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“…41 Because of the importance of hematopoietic neoplasms with germline predisposition for genetic counseling and for the detection of family members as potential donors for hematopoietic stem cell therapy, verified cases of inherited-predisposition syndromes should be documented in the patient's medical record and in the pathology report. A number of predisposing syndromes with germline mutations have been described and included in the most recent revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 8 ; the most well-known of which include AML with germline CEBPA mutation, 46,47 myeloid or lymphoid neoplasms with germline RUNX1 mutation, 48,51 myeloid or lymphoid neoplasms with germline ANKRD26 mutation, 52,53 and myeloid neoplasms with GATA2 mutation, 54,58 among others. In addition, AL arising in patients with a background of inherited bone marrow (BM) failure syndromes, such as dyskeratosis congenita and other telomerase biology diseases, and Fanconi anemia, should be recognized in the medical record.…”

Section: Strong Recommendationmentioning

confidence: 99%

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

Arber¹,

Borowitz²,

Cessna³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

100

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Context.-A complete diagnosis of acute leukemia requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and often, molecular genetic testing. Although many aspects of the workup for acute leukemia are well accepted, few guidelines have addressed the different aspects of the diagnostic evaluation of samples from patients suspected to have acute leukemia.Objective.-To develop a guideline for treating physicians and pathologists involved in the diagnostic and prognostic evaluation of new acute leukemia samples, including acute lymphoblastic leukemia, acute myeloid leukemia, and acute leukemias of ambiguous lineage.Design.-The College of American Pathologists and the American Society of Hematology convened a panel of experts in hematology and hematopathology to develop recommendations. A systematic evidence review was conducted to address 6 key questions. Recommendations were derived from strength of evidence, feedback received during the public comment period, and expert panel consensus.Results.-Twenty-seven guideline statements were established, which ranged from recommendations on what clinical and laboratory information should be available as part of the diagnostic and prognostic evaluation of acute leukemia samples to what types of testing should be performed routinely, with recommendations on where such testing should be performed and how the results should be reported.Conclusions.-The guideline provides a framework for the multiple steps, including laboratory testing, in the evaluation of acute leukemia samples. Some aspects of the guideline, especially molecular genetic testing in acute leukemia, are rapidly changing with new supportive literature, which will require on-going updates for the guideline to remain relevant.

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Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation

Cited by 44 publications

References 10 publications

Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

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