HLA class I allele–lacking leukocytes predict rare clonal evolution to MDS/AML in patients with acquired aplastic anemia

Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities

“…In 2011, Katagiri et al reported acquired copy number-neutral loss of heterozygosity of chromosome arm 6p (6pCN-LOH) involving the major histocompatibility complex region as a recurrent abnormality in AA, and were the first to propose that 6pCN-LOH clones in AA arise due to hematopoietic cells escaping autoimmune attack through HLA Class I allele loss (7). The subsequent discovery of inactivating somatic mutations in specific HLA Class I alleles unambiguously identified HLA Class I gene inactivation as a key mechanism of clonal evolution in AA that is distinct and non-cooperative with genetic mutations and cytogenetic abnormalities that drive transformation to MDS (2,4,(8)(9)(10)(11). Somatic inactivation of HLA alleles without any other mutations was sufficient for clonal expansion in AA, indicating that it was the loss of targeted alleles that created the survival advantage of HLA allele-lacking hematopoietic cells (10,(12)(13)(14).…”

“…Given the tremendous diversity of HLA alleles across racial and ethnic groups, is AA in patients of different ethnicities mediated through the same alleles and autoantigen(s)? Finally, while there has been a growing body of literature on the clinical predictive value of having somatic clones with HLA allele loss (7,11,(15)(16)(17)(18)(19), the significance of the patients' HLA Class I repertoire for development of AA and the impact that specific risk alleles play for the patients' clinical course still remain poorly understood.…”

“…Somatic inactivation of HLA alleles without any other mutations was sufficient for clonal expansion in AA, indicating that it was the loss of targeted alleles that created the survival advantage of HLA allele–lacking hematopoietic cells ( 10 , 12 – 14 ). The targeted alleles have been presumed to be responsible for AA autoantigen presentation in the affected patients; henceforth these will be referred to as “risk alleles.” Next-generation sequencing (NGS) studies of somatic HLA mutations in AA identified several such HLA class I risk alleles, most notably HLA-B* 14:02 and HLA-B *40:02, which were also significantly enriched in patients with AA ( 7 , 9 – 11 , 15 , 16 ).…”

Hypomethylating agents are associated with high rates of hematologic toxicity in patients with secondary myeloid neoplasms developing after acquired aplastic anemia

“…Up to 20% of patients go on to develop secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) 4,5 . Despite an improved understanding of CH and risk factors for post-AA myeloid neoplasms (MN) 1,3,4,[6][7][8] , optimal management of patients with post-AA MN remains unknown.…”