Mutation of cebpa in familial acute myeloid leukemia. Acute myeloid leukemia aml is a heterogeneous disease characterized by a high degree of recurrent genetic mutations, several of which have been linked to poor prognosis. In acute myeloid leukemia aml, there are too many of a specific type of white blood cell called a myeloblast. What is the prevalence of mutations in cebpa in acute myeloid. Familial acute myelogenous leukemia with mutated cebpa omim 116897. In the sporadic cases the mutation appears only in the leukemia cells, and in the familial cases it is present throughout the body. Characterization of cebpa mutations in acute myeloid.
Dec 28, 2010 purpose cebpa mutations are found as either biallelic bicebpa or monoallelic mocebpa. Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin npm1 in the same family. Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Age of onset is variable, even within the same family.
Many reports link cebpa mutations with a favorable outcome in acute myeloid leukemia. Mutations in the cebpa gene are observed in 510% of sporadic acute myeloid leukemia aml cases and are associated with a favorable outcome. Most amls with cebpa mutations simultaneously carry 2 mutations cebpa doublemut, usually biallelic, whereas single heterozygous mutations cebpa singlemut are less frequently seen. Acute myeloid leukemia with myelodysplasiarelated changes amlmrc is a heterogeneous disorder defined by morphologic, genetic, or clinical features. Unaffected family members did not have this mutation. We set out to explore whether the kind of cebpa mutation is of prognostic relevance in cytogenetically normal cn acute myeloid leukemia aml. Familial acute myeloid leukemia with mutated cebpa genetics. Mutations in the cebpa gene are observed in 510% of sporadic acute myeloid leukemia aml cases and are associated with a favorable. Carriers of a pathogenic variant develop aml at some point in their lifetime. Aml usually gets worse quickly if it is not treated.
These mutations are most frequently found in acute myeloid leukemia m1 or. Core binding factor acute myeloid leukemia cytogenetically normal acute myeloid leukemia familial acute myeloid leukemia with mutated cebpa. Acute myelogenous leukemia aml is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Jul 12, 2010 our findings confirmed mutated cebpa as a causative factor for leukaemia predisposition, however we demonstrated for the first time that mutation of this gene is not necessarily associated with a good prognosis in familial aml. Nov 09, 2018 acute myeloid leukemia, or aml, is a type of cancer that affects the bone marrow and blood. Mutation of the cebpa may play an important role in leukemogenesis and prognosis. Genetic testing for flt3, npm1, and cebpa variants to detect minimal residual disease is. Cebpa mutation is apparently the primary event in the development of aml in this family. Mar 26, 2009 mutations in ccaatenhancer binding protein. Genetic testing for the gene cebpa, which is associated with autosomal dominant familial acute myeloid leukemia aml syndrome, a condition associated with.
Currently, clinical laboratory improvement amendments approved testing exists for several myeloid leukemia predisposition syndromes. Cebpa gene mutations are identified in 1518% of cytogenetically normal aml cases leroy et al. Myeloid neoplasms and acute leukemia who 2016 acute myeloid leukemia acute myeloid leukemia with recurrent genetic abnormalities aml with mutated cebpa published date. The underlying pathophysiology in aml consists of a maturational arrest of bone marrow cells in the earliest stages of development. Cebpa are seen in 5% to 14% of acute myeloid leukemia aml and have been associated with a favorable clinical outcome most amls with cebpa mutations simultaneously carry 2 mutations cebpa doublemut, usually biallelic, whereas single heterozygous mutations cebpa singlemut are less frequently s. Acute myeloid leukemia with recurrent genetic abnormalities. Familial cebpa mutated aml represents a recognised leukemia predisposition syndrome with several families described in the literature. All three patients are currently well, with no abnormalities in the bone marrow. Although the mechanism of cell arrest is still under investigation, many individuals with aml have chromosomal translocations and other genetic abnormalities that activate or inactivate driver genes. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. Familial acute myeloid leukemia with mutated cebpa is one form of a cancer of the bloodforming tissue bone marrow called. Familial acute myeloid leukemia with mutated cebpa is a very rare form of acute myeloid leukemia. Somatic cebpa mutations are a frequent second event in families with germline cebpa mutations and familial acute myeloid leukemia. The pathological features and longterm survival of individuals with familial cebpa mutated aml are reminiscent of sporadic cebpadm aml.
Ash 2017 friday satellite symposium mds foundation. Acute myeloid leukemia aml is a cancer of the white blood cells. We reevaluated a large family with acute myeloid leukemia. A provisional diagnostic category of aml with mutated cebpa was proposed in the who classification of tumours of haematopoietic. People with familial acute myeloid leukemia with mutated cebpa have a shortage of white blood cells leukopenia, leading to increased susceptibility to infections. Another pedigree with familial acute myeloid leukemia and germline. We describe a family in whom three members affected by acute myeloid leukemia aml had an identical, 212delc mutation in cebpa, the. Whereas familial aml is considered a rare event, the frequency of cebpa germline mutations in aml is not known.
What is the pathophysiology of acute myeloid leukemia aml. Acute myeloid leukemia, or aml, is a type of cancer that affects the bone marrow and blood. In affected members of a family with acute myeloid leukemia aml. Recognizing familial myeloid leukemia in adults ncbi nih. Acute myeloid leukemia screening and prevention texas oncology. Venetoclax and quizartinib in treating patients with flt3. This is because these mutations are likely to induce differentiation arrest in these patients.
Patients with cebpa mutations have longer remission duration and survival time than those without the mutations. Mutations in the cebpa gene are found in subsets of patients with acute myeloid leukemia aml. Sep, 2017 pabst t, eyholzer m, haefliger s, schardt j, mueller bu. Familial acute myeloid leukemia with mutated cebpa is one form of a cancer of the bloodforming tissue bone marrow called acute myeloid leukemia. Invitae familial acute myeloid leukemia with mutated cebpa test 1 gene clinical sensitivity the percentage of aml attributed to pathogenic variants identified in cebpa is rare.
Between 50% and 65% of affected individuals survive their disease, compared with between 25% and 40% of people with other forms of acute myeloid leukemia. Acute myeloid leukemia aml with biallelic mutations of cebpa. Somatic mutations in other genes can also contribute to the development of cnaml. There is not a specific genotypephenotype presentation. Invitae familial acute myeloid leukemia with mutated cebpa. We describe a family in whom three members affected by acute myeloid leukemia aml had an identical, 212delc mutation in cebpa, the gene encoding the granulocytic differentiation factor cebp.
Learn about outlook and survival rates for this cancer. Mar, 2020 acute myeloid leukemia aml is a form of cancer that affects the bone marrow, which produces blood cells, and blood itself. Double cebpa mutations, but not single cebpa mutations. On the other hand, 1015% of sporadic acute myeloid leukemia with normal karyotype nkaml presents the somatic cebpa mutations. Patients and methods four hundred sixtyseven homogeneously treated patients with cnaml were subdivided into mocebpa, bicebpa, and wildtype wt cebpa.
The three different types of mutations seen in these aml patients include germline nterminal mutation, nterminal frameshift mutation, and cterminal mutation. Sep 21, 2016 purpose the transcription factor ccaatenhancer binding protein. Acute myeloid leukemia familiar with mutation cebpa familial acute myeloid leukemia with mutated cebpa gen cebpa family acute with mutation cebpa, myeloid leukemia is a form of malignancy of the bone marrow. Purpose cebpa mutations are found as either biallelic bicebpa or monoallelic mocebpa. These mutations are most frequently found in acute myeloid leukemia m1 or acute myeloid leukemia m2. We sought to characterize the cebpa mutation in acute myeloid leukemia aml and to clarify if there is a distinct immunophenotype for leukemic cells with. We describe a family in whom three members affected by acute myeloid leukemia aml had an identical, 212delc mutation in cebpa, the gene encoding the granulocytic differentiation factor cebpalpha. Cebpaassociated familial acute myeloid leukemia aml ncbi. Cebpaassociated familial acute myeloid leukemia aml is defined as aml in which a heterozygous germline cebpa pathogenic variant is present in a family in which multiple individuals have aml. Venetoclax and quizartinib in treating patients with flt3 mutated recurrent or refractory acute myeloid leukemia. Familial cebpa mutated acute myeloid leukemia aml represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004.
These mutations are most commonly found near the n terminus and result in aberrant increased production of a short protein isoform termed p30. Familial aml with mutated cebpa is an inherited autosomal dominant condition with complete or nearcomplete penetrance 11, 12. Aml with biallelic cebpa ccatenhancer binding protein alpha mutations is a distinct disease entity in the 2016 world health organization who classification of myeloid neoplasms and acute leukemia. Pedigrees for case studies of families with germline mutations in a runx1, b cebpa, c gata2, d tert, and e srp72. We also identified deletion of atm, flt3 and cdx2 genes as possible disease modifiers in familial myeloid leukaemia. Another pedigree with familial acute myeloid leukemia and. Familial acute myeloid leukemia with mutated cebpa. Familial acute myeloid leukemia aml with mutated cebpa is a hematologic malignancy predisposition syndrome that is characterized by isolated aml in the presence of a family history of aml. Occasionally, spread may occur to the brain, skin, or gums. Characterization of cebpa mutations in acute myeloid leukemia. Recently, three families were reported in whom several family members had germline cebpa mutations and subsequently developed aml. Oct 21, 2010 cebpaassociated familial acute myeloid leukemia aml is defined as aml in which a heterozygous germline cebpa pathogenic variant is present in a family in which multiple individuals have aml. Test acute myeloid leukemia aml via the cebpa gene. Testing nivolumab in combination with decitabine and venetoclax in patients with newly diagnosed tp53 gene mutated acute myeloid leukemia the safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
While acute myeloid leukemia is generally a disease of older adults, acute myeloid leukemia familiar with cebpa mutation manifested often in the early years of life. Aml is the most common type of acute leukemia in adults. Most aml subtypes are distinguished from other related blood disorders by the presence. Recognizing familial myeloid leukemia in adults eric m. Cebpa are seen in 5% to 14% of acute myeloid leukemia aml and have been associated with a favorable clinical outcome. Occasionally the diagnosis is made on routine physical examination. Familial cebpamutated acute myeloid leukemia sciencedirect. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Genetic abnormalities associated with amlmrc are often associated with adverse prognostic features, and many cases are preceded by a myelodysplastic syndrome mds or a myelodysplastic. In recent studies cebpa mutations were found in between 7% and 15% of patients with acute myeloid leukemia. Recognizing familial myeloid leukemia in adults request pdf. One of them had a second cebpa mutation, but only at the time of diagnosis.
Recognition of familial myeloid neoplasia in adults practical considerations for diagnosis and management of patients and carriers runx1 deficiency familial platelet disorder with predisposition to myeloid leukemia, fpdmm gata2 deficiency and related myeloid neoplasms familial cebpamutated acute myeloid leukemia. Acute myeloid leukaemia aml with biallelic cebpa mutations definition description of disease. Jun 02, 2014 openlabel, multidose, singlearm, multicenter, phase 12, doseescalation study to define a maximum tolerated dose and schedule mtds, describe preliminarily safety, and to assess pk, immunogenicity, immunomodulatory activity, and potential antitumor activity of flotetuzumab in patients with aml whose disease is not expected to benefit from cytotoxic chemotherapy. Genetic testing for flt3 internal tandem duplication flt3itd, npm1, and cebpa variants may be considered medically necessary in cytogenetically normal acute myeloid leukemia cnaml. In addition to advancing our therapeutic armamentarium, an increased understanding of the. Simultaneous occurrence of acute myeloid leukaemia. Aug 01, 2015 rethinking genetic profiles in acute myeloid leukemia. Its all in the cebpa mutated family saturday, august 1, 2015 though familial leukemia is rare, its prevalence is likely underestimated due to variations in disease phenotype and latency, as well as. Cebpa mutations in younger adults with acute myeloid leukemia and normal cytogenetics. This type of cancer usually gets worse quickly if it is not treated. Patients and methods four hundred sixtyseven homogeneously treated patients with cnaml were subdivided into mocebpa, bicebpa, and wildtype wt cebpa patients. Disease evolution and outcomes in familial aml with germline. Test invitae familial acute myeloid leukemia with mutated. Oct 23, 2008 mutations in the cebpa gene are observed in 510% of sporadic acute myeloid leukemia aml cases and are associated with a favorable outcome.
In contrast, sporadic cebpaassociated aml is defined as aml in which a cebpa pathogenic variants is identified in leukemic cells but not in the nonleukemic cells. The role of different genetic subtypes of cebpa mutated aml. Poor prognosis in familial acute myeloid leukaemia with. Cebpa is crucial for normal myeloid differentiation. Azacitidine, venetoclax, and gilteritinib in treating. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. The pathological features and longterm survival of individuals with familial cebpamutated aml are reminiscent of sporadic cebpadm aml. Our findings confirmed mutated cebpa as a causative factor for leukaemia predisposition, however we demonstrated for the first time that mutation of this gene is not necessarily associated with a good prognosis in familial aml. A low number of red blood cells anemia also occurs in this disorder, resulting in fatigue and weakness.
These inherited mutations are present throughout a persons life in virtually every cell in the body. The cebpa gene is associated with autosomal dominant familial acute myeloid leukemia medgen uid. Test invitae familial acute myeloid leukemia with mutated cebpa. Gata2 mutations in sporadic and familial acute myeloid. Latent periods of 10, 18, and 30 years elapsed before the onset of overt leukemia in the three patients. Somatic cebpa mutations are a frequent second event in. At least six mutations in the cebpa gene have been identified in families with familial acute myeloid leukemia with mutated cebpa, which is a form of a blood cancer known as acute myeloid leukemia. Disease evolution and outcomes in familial aml with. People with familial acute myeloid leukemia with mutated cebpa have a shortage of white blood cells leukopenia, leading to increased susceptibility to. Safety study of mgd006 in relapsedrefractory acute myeloid. Cebpaassociated familial acute myeloid leukemia aml. Index case of acute myeloid leukemia in a family harboring a. Only a few cases of familial aml have been reported smith et al.
Acute myeloid leukemia mutation information aml mutations. Familial cebpamutated acute myeloid leukemia aml represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004. Mutation of cebpa in familial acute myeloid leukemia nejm. Oct 28, 2019 this phase iii trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with flt3mutation positive acute myeloid leukemia or highrisk myelodysplastic syndrome that has come back recurrent or has not responded to treatment refractory. Familial acute myeloid leukemia aml with mutated ccaatenhancerbinding protein. Acute myeloid leukemia aml is usually diagnosed because patients have signs and symptoms of leukemia, including fatigue, weight loss, bleeding, easy bruising, or unexplained infections. Familial acute myeloid leukemia is rare and linked to germline mutations in runx1, gata2 or ccaatenhancer binding proteina cebpa. The transcription factor ccaatenhancer binding protein.
Familial acute myeloid leukemia with mutated cebpa disease. Currently, four recognized syndromes could be separated. Pdf index case of acute myeloid leukemia in a family. Myeloid neoplasms and acute leukemia who 2016 acute myeloid leukemia acute myeloid leukemia with recurrent genetic abnormalities aml with mutated cebpa. Genetic testing family acute myeloid leukemia with mutation. Acute myeloid leukemia with biallelic cebpa gene mutations. Gata2 mutations have recently been reported in acute myeloid leukaemia aml patients with cebpa. Green cebpa in inherited predisposition to acute myeloid leukaemia aml version 1. Its all in the cebpamutated family saturday, august 1, 2015 though familial leukemia is rare, its prevalence is likely underestimated due to variations in disease phenotype and latency, as well as a lack of systematically collected data on family history. Mutation of cebpain familial acute myeloid leukemia.
Acute myeloid leukemia aml results from the maturational arrest of bone marrow cells in the earliest stages of development. Familial acute myeloid leukemia with mutated cebpa at least six mutations in the cebpa gene have been identified in families with familial acute myeloid leukemia with mutated cebpa, which is a form of a blood cancer known as acute myeloid leukemia. Acute myeloid leukemia aml is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. Gata2 mutations in sporadic and familial acute myeloid leukaemia patients with cebpa mutations. Acute myeloid leukaemia aml with biallelic cebpa mutations definition description of disease aml with biallelic cebpa ccatenhancer binding protein alpha mutations is a distinct disease entity in the 2016 world health organization who classification of myeloid neoplasms and acute leukemia 1. Genetic testing family acute myeloid leukemia with. Familial cebpamutated aml displays a unique model of disease progression. Normal blood marrow produces immature blood cells called hematopoietic stem cells that evolve into many different blood cells such as white blood cells that fight infection, red blood cells that carry oxygen, and. Testing nivolumab in combination with decitabine and.
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