Clonal evolution in aplastic anemia: failed tumor surveillance or maladaptive recovery?

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…Immune exhaustion in adaptation to persistent inflammatory stimulation is a common mechanism underlying the escape of leukemic clones from immune surveillance ( 17 , 18 ). Hyporesponsiveness is characterized by a high infiltration of negative immune cells, excessive secretion of anti-inflammatory cytokines by immune regulatory cells, and high expression of immune checkpoint molecules on tumor cells in the tumor microenvironment, which work to limit the magnitude of inflammatory responses, avoid excessive tissue damage, and maintain a dynamic immune balance in the context of chronic inflammatory stressors ( 272 , 273 ).…”

“…During infectious episodes, patients demonstrate positive immune responses and frequently experience an aplastic crisis. After successful treatment of underlying infections, dampened inflammatory stress-powered antileukemic immunity leads to the expansion of previously suppressed leukemic clones and facilitates the appearance of symptomatic MNs, which is distinct from the naturally occurring clonal evolution in AA ( 11 – 14 ) due to the acquisition of novel somatic mutations and immune exhaustion in the chronic inflammatory milieu ( 16 , 17 , 321 , 323 ).…”

“…Along with disease progression, the immunological signature in the BME is transformed from a Th1-predominant response to an immune exhaustion state in which the function of infiltrated autoimmune lymphocytes is inhibited and immune surveillance is gradually dampened in adaptation to the chronic inflammatory milieu. The immune exhaustion state favors leukemic cell survival and facilitates the penetration of symptomatic MNs (15)(16)(17)(18). The extrapolation was mainly drawn from tumor regression and concomitant autoimmune phenomena in diseased organs during the treatment of non-hematological malignancies with immunological therapy.…”

“…While hMDS is an unequivocal MN, AA has a high frequency of transformation to MNs. The natural evolution from AA to MNs is usually a long-term process (11)(12)(13)(14) and is frequently attributed to genetic damage or immune exhaustion due to an inflamed BME (15)(16)(17)(18). However, leukemic transformation can occur during or shortly after IST (19)(20)(21)(22)(23).…”

Acquired Aplastic Anemia Therapies: Immunosuppressive Therapy Versus Alternative Donor Hematopoietic Cell Transplantation

“…Human leukocyte antigen (HLA) class I alleles, such as HLA-B*14:02, occur at greater frequency in patients with autoimmune disease, such as AA [ 4 ]. HLA molecules and other major histocompatibility complex-like molecules, such as glycosylphosphatidylinositol (GPI), present pathogenic antigens that unleash an immune attack by CD8 + cells resulting in diminished HSPC in the marrow of AA patients [ 5 , 6 ]. The precise antigen specificity that launches this immune attack is unknown but may be viral, such as hepatitis [ 6 ].…”