When Blood Disorders Meet Cancer: Uncovering the Oncogenic Landscape of Sickle Cell Disease

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, vaso-occlusion, and systemic inflammation. Epidemiological studies identified an increased risk of leukemia, especially acute myeloid leukemia (AML), in individuals with SCD, whereas data regarding other tumors are conflicting. SCD-associated AMLs frequently display high-risk features with unfavorable karyotypes and a dismal prognosis. SCD is associated with multiple phenomena linked to carcinogenesis in other contexts, including chronic inflammation, oxidative stress, ineffective erythropoiesis, accelerated hematopoietic aging, impaired tumor immunosurveillance, and increased clonal hematopoiesis. The role and respective contribution of these disease-intrinsic mechanisms in SCD remain to be studied. Although therapies used in SCD could theoretically modulate the risk of malignancies, no data exist to support an increased or reduced risk associated with their use. The most notable exception is hematopoietic stem cell transplantation and, to a lesser extent, gene therapy, for which the conditioning and/or procedure itself is known to increase the risk of leukemia. In sum, the effect of SCD on carcinogenesis is an emerging area of investigation with data supporting specificities in SCD-associated AML. Future research is required to determine the role of treatments to mitigate the increased risk and improve the outcome of SCD-associated AML.