Mutations of ASXL1 and TET2 in aplastic anemia

Huang, Jinbo; Ge, Meili; Lu, Shihong; Shi, Jun; Li, Xingxin; Zhang, Jizhou; Wang, Min; Yu, Wei; Shao, Yijun; Huang, Zhendong; Zhang, Jing; Nie, Neng; Zheng, Yizhou

doi:10.3324/haematol.2014.120931

Cited by 40 publications

(35 citation statements)

References 14 publications

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“…Available studies, many of which included post-AA MDS patients, indicate that acquired mutations in ASXL1 and DNMT3A are associated with a worse overall survival and with an increased risk of malignant transformation; importantly, the majority of patients harboring these mutations did not progressed to MDS over the limited study period [94,97,98]. Conversely, mutations in PIGA and BCOR/BCORL1 genes have been linked to a more favorable prognosis [98].…”

Section: Clonal Hematopoiesis and Mds Predisposition In Acquired Aplamentioning

confidence: 99%

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Babushok

Bessler

Olson

2015

Leukemia & Lymphoma

104

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Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

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Section: Clonal Hematopoiesis and Mds Predisposition In Acquired Aplamentioning

confidence: 99%

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Babushok

Bessler

Olson

2015

Leukemia & Lymphoma

104

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“…8 More recently, the issue has been newly addressed by using revolutionized sequencing technologies, unmasking a unique picture of CH in AA frequently accompanied by somatic mutations commonly seen in myeloid malignancies. [13][14][15][16][17][18] Combined with seminal findings on CH in aged normal individuals, [19][20][21] as well as on preleukemic clones 22 in patients with hematologic malignancies, [23][24][25] the finding on somatic mutations in AA provides new insight into the origin and the mechanism of frequent CH in AA and its impact on the late development of MDS and AML. 13,15,18 This review summarizes recent progress in the current understanding of CH in AA in relation to the pathogenesis of late clonal diseases.…”

Section: Medscape Continuing Medical Education Onlinementioning

confidence: 99%

“…The revolutionized technologies of next-generation DNA sequencing (NGS), together with the accumulated knowledge about the major driver mutations in MDS/AML, 42,64 have prompted investigations on somatic mutations in AA in relation to clonal evolution to MDS/AML. Thus, since the first report by Lane et al, 13 there have been several NGS-based mutation studies on AA during the past 2 years reporting varying mutation frequencies ranging from 5.3% to 72% [13][14][15][16][17][18] (Table 1). Among these studies, mutations were most comprehensively studied by Yoshizato et al, who surveyed mutations in 106 genes commonly mutated in myeloid cancers in 439 patients using targeted-capture deep sequencing.…”

Section: Skewed X-chromosome Inactivationmentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

162

130

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Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

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“…Using targeted NGS of genes recurrently mutated in hematologic malignancies, several groups identified somatic mutations in MDS-associated genes in AA, detected in up to a third of adult AA patients [80–83, 66]. The most commonly mutated malignancy-associated genes in AA are ASXL1 , BCOR / BCORL1 , and DNMT3A [66, 81, 82].…”

Section: Clonal Evolutionmentioning

confidence: 99%

Diagnosis and Treatment of Aplastic Anemia

Peslak

Olson

Babushok

2017

Curr. Treat. Options in Oncol.

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Opinion Statement Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with upfront closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long term clonal complications.

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Mutations of ASXL1 and TET2 in aplastic anemia

Cited by 40 publications

References 14 publications

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Clonal hematopoiesis in acquired aplastic anemia

Diagnosis and Treatment of Aplastic Anemia

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