Genetic and cellular origins of histiocytic neoplasms

Abstract

Histiocytic neoplasms are rare blood disorders characterized by clonal cells with a monocyte, macrophage, or dendritic cell phenotype. These cells are generally infrequent in the blood but tend to accumulate and form destructive lesions in tissues such as the bone and skin. Histiocytic neoplasms may affect both children and adults and range from benign neoplasms to highly aggressive cancers. In this thesis, the genetic and cellular origins of these heterogeneous diseases were explored, revealing that certain genetic drivers are linked to specific disease subtypes. This finding advances the molecular understanding of histiocytic neoplasms and paves the way for their genetic subclassification and personalized, molecularly-guided treatment. In addition, the work in this thesis demonstrates that diverse histiocytic neoplasms may originate from mutated hematopoietic stem/progenitor cells, including those confined to a single organ. The mutated progenitors may give rise to additional, clonally related hematologic neoplasms, particularly in adults. Fortunately, several studies in this thesis show that the mutated histiocytic cells can be effectively targeted by kinase inhibitors, marking a breakthrough in the clinical management of these rare blood disorders.