Aplastic anemia and clonal evolution: germ line and somatic genetics

Abstract

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.

The histopathology of bone marrow failure in children

“…23 The clinical significance of other isolated nonspecific abnormalities remains unclear. 28 BM biopsy evaluation is indispensable for an AA diagnosis, 26 allowing for correct evaluation of BM cellularity and histological discrimination of AA from RCC. 4 The BM histological criteria for AA and hypoplastic RCC are compared in Table 1B.…”

Autoimmune and other acquired neutropenias

“…Although specific phenotypes may inform single gene or gene family sequencing, 3 these panels provide an expensive (but actually cost-effective compared to multiple single-gene analyses) means to assess the multiple genes responsible for a wide array of variable phenotypes of congenital neutropenia and bone marrow failure syndromes. 4 …”

Molecular pathogenesis of acquired aplastic anemia

“…Specific mutations have been associated with differing clinical outcomes such as their impact on response to immunosuppressive therapy (IST), progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), and survival. [2][3][4] Their clinical significance is seemingly informed by the specific gene 4 and nature of the mutation involved, 5 clonal size dynamics (mutational allele burden), 6 mutational hierarchy (ie, somatic ancestral events vs sub-clonal events), 5 and variant allelic fraction progression over time. 4,6 These mutations mark clonally derived populations in a HSC mosaicism, and serve as valuable markers for monitoring clonal dynamics of the stem cell compartment and in predicting MDS/AML evolution.…”