Clonal hematopoiesis in acquired aplastic anemia

Ogawa, Seishi

doi:10.1182/blood-2016-01-636381

Cited by 159 publications

(145 citation statements)

References 88 publications

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“…Because structural variation at the MHC locus is a likely substrate for somatic rearrangements in cells of the immune system, derogated repair of MHC rearrangements may facilitate their clonal proliferation in FA cells. Interestingly, copy-neutral loss of heterozygosity in 6p by UDP involving the MHC locus has been reported in acquired aplastic anemia 27 and primary nervous system lymphoma. 28 Loss of the mismatched HLA haplotype by UPD has also been found after haploidentical hematopoietic stem cell transplantation and infusion of donor T cells in leukemic patients, leading to relapse through the escape of leukemic cells from the donor's antileukemic T cells.…”

Section: Discussionmentioning

confidence: 99%

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

et al. 2017

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Key Points• Fanconi anemia patients have exacerbated cytogenetic clonal mosaicism as detected by molecular karyotyping of blood DNA with SNP assays.• Bone marrow clonal abnormalities can be detected in blood DNA and used as biomarkers of cancer risk and poor prognosis.Detectable clonal mosaicism for large chromosomal events has been associated with aging and an increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders, such as Fanconi anemia (FA), could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by single-nucleotide polymorphism ( ). Therefore, our data suggest that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk, and overall survival of FA patients.

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Section: Discussionmentioning

confidence: 99%

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

et al. 2017

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“…[24][25][26][27] This condition has been defined as age-related clonal hematopoiesis or clonal hematopoiesis of indeterminate potential. 15,28,29 In this work, we performed a mutation analysis of genes that are recurrently mutated in myeloid malignancies in a prospective cohort of individuals with unexplained cytopenia undergoing a comprehensive diagnostic workup, with the aim to estimate the predictive value of somatic mutations for identifying individuals with a myeloid neoplasm or with an increased risk of developing these malignancies.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of somatic mutation in unexplained blood cytopenia

Malcovati

Gallì

Travaglino

et al. 2017

Blood

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406

419

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Key Points• Mutation profiling has a high predictive value for identifying individuals with, or at high risk of developing, a myeloid neoplasm.• Patients with clonal cytopenia have a significantly higher risk of developing a myeloid neoplasm than those with no evidence of clonality.Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency ‡0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio 5 13.9, P < .001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia and more generally the diagnostic accuracy of myeloid neoplasms. (Blood. 2017;129(25):3371-3378)

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“…In fact, an unsolved mystery of PNH is what determines the extent to which the PIGA-mutant clone expands. [4][5][6][7][8] This question is framed by in vitro and in vivo studies demonstrating that mutant PIGA alone is insufficient to account for clonal expansion.…”

Section: Introductionmentioning

confidence: 99%

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria

Parker

2016

Hematology

123

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Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells. Bone marrow failure complicates management of PNH because compromised erythropoiesis contributes, to a greater or lesser degree, to the anemia; in addition, the extent to which the mutant stem cell clone expands in an individual patient determines the magnitude of the hemolytic component of the disease. An understanding of the unique pathobiology of PNH in relationship both to complement physiology and immune-mediated bone marrow failure provides the basis for a systematic approach to management.

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Clonal hematopoiesis in acquired aplastic anemia

Cited by 159 publications

References 88 publications

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

Clinical significance of somatic mutation in unexplained blood cytopenia

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria

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