Abstract
Histiocytic sarcoma is a rare, aggressive neoplasm that responds poorly to therapy. Histiocytic sarcoma is thought to arise from macrophage precursor cells via genetic changes that are largely undefined. To improve our understanding of the etiology of histiocytic sarcoma we conducted a forward genetic screen in mice using the Sleeping Beauty transposon as a mutagen to identify genetic drivers of histiocytic sarcoma. Sleeping Beauty mutagenesis was targeted to myeloid lineage cells using the Lysozyme2 promoter. Mice with activated Sleeping Beauty mutagenesis had significantly shortened lifespan and the majority of these mice developed tumors resembling human histiocytic sarcoma. Analysis of transposon insertions identified 27 common insertion sites containing 28 candidate cancer genes. Several of these genes are known drivers of hematological neoplasms, like Raf1, Fli1, and Mitf, while others are well-known cancer genes, including Nf1, Myc, Jak2, and Pten. Importantly, several new potential drivers of histiocytic sarcoma were identified and could serve as targets for therapy for histiocytic sarcoma patients.
Highlights
Histiocytic sarcoma (HS) is classified as a neoplastic proliferation with features of histiocytes/macrophages[1]
The Sleeping Beauty (SB) transposon consists of terminal inverted and direct repeats required for SB transposition and an internal promoter, splice donor, splice acceptors and bidirectional polyA signal
After correcting for multiple testing, we found significant associations between Fli1 and Bach2 and between Mitf and Raf1, suggesting these pairs of mutations may cooperate in HS tumorigenesis, formal proof of cooperation would require further experiments
Summary
Histiocytic sarcoma (HS) is classified as a neoplastic proliferation with features of histiocytes/macrophages[1]. HS has been called true histiocytic lymphoma or malignant histiocytosis, but these terms have been discontinued. Before 1990, the majority of patients diagnosed with HS were misdiagnosed due to a lack of antibodies specific for the histiocytic lineage. Retrospective analysis indicated the majority of these patients had Bor T-cell lymphomas[2,3,4,5]. Case studies have demonstrated that HS can occur in isolation or in the context of other hematological malignancies, such as B-cell lymphoma, to which the HS is sometimes clonally related[4]. HS may in some cases, develop via trans-differentiation from a malignant, or premalignant, lymphoid neoplasm. Since the genetic etiology of HS is largely unknown, HS is difficult to manage clinically and there is no standard therapy for patients with HS
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