Clinical significance of acquired somatic mutations in aplastic anaemia

Marsh, Judith; Mufti, Ghulam J.

doi:10.1007/s12185-016-1972-8

Cited by 13 publications

(8 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Irrespective of the inciting stimulus, the initial immune response is characterized by increase in CD4+ T helper cells, CD8+ T cells, Th‐17 cells, and decrease in T‐reg cells resulting in oligoclonal expansion of CD8+ T cells . The immune signature that occurs with the acquisition of SMs has yet to be characterized and is an area of active investigation …”

Section: The T‐cell Repertoirementioning

confidence: 99%

Molecular pathogenesis of acquired aplastic anemia

Boddu

Kadia

2018

European J of Haematology

View full text Add to dashboard Cite

The application of next‐generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)‐associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA‐related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.

show abstract

Section: The T‐cell Repertoirementioning

confidence: 99%

Molecular pathogenesis of acquired aplastic anemia

Boddu

Kadia

2018

European J of Haematology

View full text Add to dashboard Cite

show abstract

“…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%

Diagnosis and Treatment of Aplastic Anemia

Peslak

Olson

Babushok

2017

Curr. Treat. Options in Oncol.

View full text Add to dashboard Cite

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.

show abstract

“…26,27 The implications of clonal hematopoiesis for disease pathogenesis and progression to MDS or AML in marrow failure is being actively investigated. The potential role of immunologic targeting of the bone marrow to promote clonal evolution in AA has recently been reviewed and will not be discussed here.…”

Section: Bmf: Somatic Geneticsmentioning

confidence: 99%

“…The potential role of immunologic targeting of the bone marrow to promote clonal evolution in AA has recently been reviewed and will not be discussed here. 26 Studies of clonal hematopoiesis in acquired AA and in inherited marrow failure disorders are considered separately.…”

Section: Bmf: Somatic Geneticsmentioning

confidence: 99%

See 1 more Smart Citation

Aplastic anemia and clonal evolution: germ line and somatic genetics

Shimamura

2016

Hematology

View full text Add to dashboard Cite

Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.

show abstract

Clinical significance of acquired somatic mutations in aplastic anaemia

Cited by 13 publications

References 40 publications

Molecular pathogenesis of acquired aplastic anemia

Molecular pathogenesis of acquired aplastic anemia

Diagnosis and Treatment of Aplastic Anemia

Aplastic anemia and clonal evolution: germ line and somatic genetics

Contact Info

Product

Resources

About