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Sequencing Offers Clues to Clonal Evolution in Aplastic Anemia

In a study published online today in the New England Journal of Medicine, researchers from the US and Japan described mutation and clonal dynamic patterns in aplastic anemia — a non-cancerous condition involving an immune  attack on blood system cells that sometimes progresses to myelodysplastic syndrome and/or acute myeloid leukemia (AML).

Using a combination of exome sequencing, targeted sequencing, and array-based karyotyping, the team scrutinized somatic mutation profiles in blood samples from more than 400 individuals with aplastic anemia, including 82 individuals tested at more than one time point.

With these data, the researchers saw expansion of hematopoietic cell clones in nearly half of those with aplastic anemia. In roughly one-third of the cases, they detected mutations associated with myelodysplastic syndrome and/or AML.

At least some of the mutations showed apparent ties to subsequent treatment response and survival, though the study's authors cautioned that "the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative."

Bone marrow transplantation and immunosuppression therapy are being used to successfully treat or even cure many aplastic anemia cases, the team explained. But around 15 percent of patients still progress to myelodysplastic syndrome and/or AML — a process that appears to involve the evolution and expansion of particular mutation-containing clones.

Alternatively, clonal expansion of hematopoietic stem cell clones that contain somatic mutations can also lead to a non-myelodysplastic/AML disease such as paroxysmal nocturnal hemoglobinuria, the researchers noted.

In an effort to begin teasing apart the clonal characteristics accompanying these distinct disease trajectories, they used sequencing to assess mutations present in 668 blood samples from 439 aplastic anemia patients.

The investigators did targeted gene panel sequencing on blood samples from all the participants, focusing on a panel of 106 genes previously implicated in myeloid cancers, which were sequenced to 1,248-fold coverage, on average.

From those sequences, they found somatic mutations in 156 of the individuals, including 56 individuals who carried two or more different gene mutations. When mutations were present, more than three-quarters of them fell in just a handful of genes such as BCOR, BCPRL1, PIGA, DNMT3A, and ASXL1.

A chromosome 6 glitch linked to paroxysmal nocturnal hemoglobinuria development turned up in more than a tenth of the cases.

Mutations were more numerous in older individuals, the researchers reported. Most alterations occurred at lower frequencies than in full-blown AML or myelodysplastic syndrome, though they saw an over-representation of aplastic anemia-related mutations affecting PIGA, BCOR, and BCOR1.

When they did exome sequencing on 135 samples taken over time from 52 individuals with aplastic anemia, with an average of 112-fold coverage of the protein-coding portions of their genomes, the researchers uncovered somatic mutation events in 25 cases.

Their results suggest aplastic anemia progression often involved a decline in or maintenance of clones containing BCOR, BCORL1, or PIGA gene mutations, while clones characterized by DNMT3A and/or ASXL1 mutations typically expanded.

The presence of mutations in genes such as DNMT3A, ASXL1, and RUNX1 coincided with poorer progression-free survival and overall survival times. In contrast, BCOR and BCORL1 mutations corresponded to favorable outcomes following immunosuppression therapy.

Still, the researchers noted that clonal dynamics appear to be quite variable, making prognostic patterns difficult to decipher. Such predictions may be further complicated by the accumulation of age-related mutations in the blood cell system.

"Close monitoring of clonal hematopoiesis by means of both deep sequencing and SNP array karyotyping will need to be combined with clinical evaluation to estimate prognosis and to guide treatment of patients with aplastic anemia," they concluded.

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