Recent advances in understanding clonal haematopoiesis in aplastic anaemia

Stanley, Natasha; Olson, Timothy S.; Babushok, Daria V.

doi:10.1111/bjh.14510

Cited by 57 publications

(51 citation statements)

References 113 publications

(243 reference statements)

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“…HSCs with these mutations may have survival advantages by being less immunogenic as evidenced by more frequent PIGA mutations and may have a higher chance for recruitment especially when the pool of HSCs is depleted. [85][86][87] Other than PIGA mutations, the most frequently detected somatic mutations in AA are in that in BCOR, BCORL1, and the MDS-related somatic mutations in DNMT3A and ASXL1, which in one study cumulatively accounted for 77% of all somatic mutation-positive patients.…”

Section: S O M Ati C M Utati O N Smentioning

confidence: 99%

Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

Shallis

Ahmad

Zeidan

2018

European J of Haematology

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Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen-driven and likely autoimmune dysregulated T-cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such as TERT and TERC. In addition, recurring mutations in BCOR/BCORL, PIGA, DNMT3A, and ASXL1 as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.

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Section: S O M Ati C M Utati O N Smentioning

confidence: 99%

Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

Shallis

Ahmad

Zeidan

2018

European J of Haematology

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“…~15% of AA patients treated with IST go on to develop the late complications of MDS and acute myeloid leukemia (AML) [64, 65, 43]. Approximately 10% of AA patients (range 3–26%) develop cytogenetic changes during the course of their disease (reviewed in [7]), most commonly monosomy 7/del (7q) and trisomy 8, as well as del (13q), and trisomies of chromosomes 6, 15 and 21. In the context of AA, monosomy 7 has been found to correlate with a poor prognosis, including a worse response to IST and increased progression to MDS, while del (13q) and trisomy 8 are associated with an improved response to IST and a better prognosis (reviewed in [6, 7]).…”

Section: Clonal Evolutionmentioning

confidence: 99%

“…The majority of AA patients, including over 60% of children with AA, develop clonal genetic changes [66, 67]. Several recent reviews comprehensively addressed this topic [6, 7, 68]. The most common clonal abnormality in AA is the development of PNH clones, which can be detected by flow cytometry as cells lacking glycophophatidyl-inositol-linked proteins due to a somatic mutation in the PIGA gene [69, 70], found in up to 50% of AA patients.…”

Section: Clonal Evolutionmentioning

confidence: 99%

“…In pediatric patients, new transplant strategies and improvements in supportive care have led to greatly improved outcomes and increasing use of BMT in both upfront and refractory settings [5]. Furthermore, recent recognition of frequent clonal hematopoiesis in AA has changed our understanding of this immune-mediated blood disorder, reframing how we view somatic changes and a diagnosis of myelodysplastic syndrome (MDS) in patients with AA [6, 7]. Here, we present a comprehensive review of the diagnosis and treatment of AA, focusing on recent studies.…”

Section: Introductionmentioning

confidence: 99%

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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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“…TNFα and IFNγ); d) severe reduction and functional impairment of immunosuppressive regulatory T cells (Tregs); and e) karyotype abnormalities, genomic instability, and somatic mutations in different myeloid cancer-associated genes that positively and negatively correlate with response to immunosuppresive therapy (IST) and risk of development of myelodysplasia and acute myeloid leukemia (AML). [2][3][4][5][6] Current standard treatments for AA include IST with horse anti-thymocyte globulin (ATG) and cyclosporine A (CsA), or allogeneic HLA-matched sibling or well-matched unrelated donor BM transplant. While IST is effective in 60-70% of AA patients, a significant proportion of patients who responded to IST undergo relapse after CsA withdrawal or are refractory to IST.…”

mentioning

confidence: 99%