Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia

Yoshizato, Tetsuichi; Dumitriu, Bogdan; Hosokawa, Kohei; Makishima, Hideki; Yoshida, Kenichi; Townsley, Danielle M.; Sato‐Otsubo, Aiko; Sato, Yusuke; Liu, Delong; Suzuki, Hiromichi; Wu, Colin O.; Shiraishi, Yuichi; Clemente, Michael J.; Kataoka, Keisuke; Shiozawa, Yusuke; Okuno, Yusuke; Chiba, Kenichi; Tanaka, Hiroko; Nagata, Yasunobu; Katagiri, Takamasa; Kon, Ayana; Sanada, Masashi; Scheinberg, Phillip; Miyano, Satoru; Maciejewski, Jaroslaw P.; Nakao, Shinji; Young, Neal S.; Ogawa, Seishi

doi:10.1056/nejmoa1414799

Cited by 511 publications

(582 citation statements)

References 41 publications

(34 reference statements)

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“…On the other hand, somatic mutations in genes associated with myeloid neoplasms (such as DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1, and SF3B1) have been frequently found in aging healthy individuals. [10][11][12]29 MDS-associated somatic mutations and clonal hematopoiesis have been recently reported in near half of patients with aplastic anemia, 30 as well as in patients with idiopathic cytopenias of undetermined significance. 29,31 In the latter, variant allele fractions were comparable with MDS.…”

Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

et al. 2016

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The distinction between chronic eosinophilic leukemia, not otherwise specified and idiopathic hypereosinophilic syndrome largely relies on clonality assessment. Prior to the advent of next-generation sequencing, clonality was usually determined by cytogenetic analysis. We applied targeted next-generation sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of idiopathic hypereosinophilic syndrome patients (n = 51), and assessed the significance of mutations in conjunction with clinicopathological features. The findings were further compared with those of 17 chronic eosinophilic leukemia, not otherwise specified patients defined by their abnormal cytogenetics and/or increased blasts. Mutations were detected in 14/51 idiopathic hypereosinophilic syndrome patients (idiopathic hypereosinophilic syndrome/next-generation sequencing-positive) (28%), involving single gene in 7 and ≥ 2 in 7 patients. The more frequently mutated genes included ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%). Idiopathic hypereosinophilic syndrome/next-generation sequencing-positive patients showed a number of clinical features and bone marrow findings resembling chronic eosinophilic leukemia, not otherwise specified. Chronic eosinophilic leukemia, not otherwise specified patients showed a disease-specific survival of 14.4 months, markedly inferior to idiopathic hypereosinophilic syndrome/next-generation sequencing-negative (P o0.001), but not significantly different from idiopathic hypereosinophilic syndrome/next-generation sequencing-positive (P = 0.117). These data suggest that targeted next-generation sequencing helps to establish clonality in a subset of patients with hypereosinophilia that would otherwise be classified as idiopathic hypereosinophilic syndrome. In conjunction with other diagnostic features, mutation data can be used to establish a diagnosis of chronic eosinophilic leukemia, not otherwise specified in patients presenting with hypereosinophilia.

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Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

et al. 2016

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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: 91%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

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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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“…Our previous study used a SNP array analysis to reveal that approximately 13% of AA patients had 6pLOH(+) cells [9,10]. However, the involvement of the lineage of HLA-LLs in 6pLOH(+) patients remained unclear due to the limited number of patients whose leukocytes were analyzed with FCM.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we successfully isolated a T-cell clone that was capable of killing hematopoietic cells in an HLA-B*40:02-restricted manner from one of the 6pLOH(+) patients (case 8) [7]. On the other hand, a recent analysis of 256 severe AA patients, including 33 6pLOH(+) patients, who were treated with horse ATG in the United States failed to show a better response rate in comparison to 6pLOH(-) patients [10]. Another recent study by Betensky et al detected 6pLOH in eight (11.3%) of 71 patients with bone marrow failure using a SNP array analysis and found no significant difference in the response rate to IST between 6pLOH(+) patients and 6pLOH(-) patients (50% v. 77.8%) [24].…”

Section: Discussionmentioning

confidence: 99%

“…Single nucleotide polymorphism (SNP) array analysis reveals the copy number-neutral loss of heterozygosity of the HLA haplotype due to uniparental disomy in the short arm of chromosome 6 (6pLOH) in approximately 13% of AA patients [8][9][10]. Flow cytometry (FCM) can be substituted for SNP array for detection of HLA-A allele-lacking leukocytes (HLA-LLs) as a result of 6pLOH, because 6pLOH was revealed in all HLA-LL(+) patients in our previous study [9].…”

Section: In Vivomentioning

confidence: 99%

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