Genetic characterization of acquired aplastic anemia by targeted sequencing

• Accelerated telomere attrition precedes chromosomal loss and malignant transformation to MDS/AML arising from aplastic anemia.The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to 27, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of 27. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy. (Blood. 2015;125(4):706-709)

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“…[14][15][16] In the largest reported cohort of 150 AA patients, 14 17 had clonal evolution, but only 4 patients had 27 MDS.…”

Section: Resultsmentioning

confidence: 99%

Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia

Dumitriu

Feng

Townsley

et al. 2015

Blood

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“…DNMT3A and ASXL1 mutations tend to increase their clone size over years, whereas BCOR/BCORL1 and PIGA mutations are likely to show a decreasing or stable clone size. Generally, frequency and the mean number of mutations increase with age, which is not 13 Kulasekararaj et al 15 Heuser et al 14 Babushok et al 16 Yoshizato the case for the latter set of mutations. As a whole, mutations do not significantly affect response to IST, progression to MDS/AML, or overall survival.…”

Section: Characteristics Of Mutations In Aamentioning

confidence: 99%

“…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%

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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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“…The MAB was <10 % in 7 patients [23]. Heuser et al found 3 mutations in 2 of 38 patients (SLIT1, and SETBP1 with ASXL1) using a smaller panel of 42 genes and excluding SM with a MAB of <15 % [24]. However, the patient with SETBP1 and ASXL1 was tested at time of progression to MDS.…”

Section: Somatic Mutations In Aamentioning

confidence: 99%

Clinical significance of acquired somatic mutations in aplastic anaemia

Marsh

Mufti

2016

Int J Hematol

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haemopoietic stem cell (HSC) disorders, most commonly paroxysmal nocturnal haemoglobinuria (PNH). It may later evolve to myelodysplastic syndrome (MDS) in up to 15-20 % of patients [1][2][3]. Furthermore, there is overlap between AA and MDS in the form of the entity hypocellular MDS which is often difficult to distinguish from AA on morphological criteria, especially when AA is of the nonsevere sub-type [4]. Because AA may be associated with an abnormal cytogenetic clone in up to 12 % of patients, the finding of an abnormal cytogenetic clone does not always help in differentiating AA from hypocellular MDS, although the finding of monosomy 7 usually indicates MDS instead of AA [5]. There are specific acquired somatic mutations (SMs) that characterise these overlapping bone marrow failure (BMF) disorders, in addition to mutations of PIGA that occur in PNH. Acquired STAT3 mutations occur in 40 % of patients with T-large granular lymphocytosis (T-LGL) but can also be detected in 7 % of AA and 3 % of MDS patients with unsuspected T-LGL, that is, with subclinical T-LGL clones.[6] Lastly, SMs that typify MDS and acute myeloid leukaemia (AML) have recently been reported in AA, and which are the main focus of this mini review [7,8]. Expansion of clones that escape immune attack in aplastic anaemiaUnderlying this clonal haemopoiesis is an important interaction with the immune response that occurs in AA resulting in expansion and a proliferative advantage of certain clones that can evade the immune attack, and contribute to haemopoiesis [1][2][3]. This is best exemplified by PIGA mutated HSC. Data supporting an intrinsic survival advantage of PNH HSCs are lacking. Instead, the expansion of PNH clones in AA is more likely due to an extrinsic factor, for example, immune attack, whereby PNH HSCs are Abstract Aplastic anaemia (AA) is frequently associated with other disorders of clonal haemopoiesis such as paroxysmal nocturnal haemoglobinuria (PNH), myelodysplastic syndrome (MDS) and T-large granular lymphocytosis. Certain clones may escape the immune attack within the bone marrow environment and proliferate and attain a survival advantage over normal haemopoietic stem cells, such as trisomy 8, loss of heterozygosity of short arm of chromosome 6 and del13q clones. Recently acquired somatic mutations (SM), excluding PNH clones, have been reported in around 20-25 % of patients with AA, which predispose to a higher risk of later malignant transformation to MDS/ acute myeloid leukaemia. Furthermore, certain SM, such as ASXL1 and DNMT3A are associated with poor survival following immunosuppressive therapy, whereas PIGA, BCOR/ BCORL1 predict for good response and survival. Further detailed and serial analysis of the immune signature in AA is needed to understand the pathogenetic basis for the presence of clones with SM in a significant proportion of patients.

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Genetic characterization of acquired aplastic anemia by targeted sequencing

Cited by 52 publications

References 21 publications

Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia

Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia

Clonal hematopoiesis in acquired aplastic anemia

Clinical significance of acquired somatic mutations in aplastic anaemia

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