Malignant progression of an ancestral bone marrow clone harboring a CIC-NUTM2A fusion in isolated myeloid sarcoma

Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia (AML) or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase signaling activation when compared to other fusion driven murine AML models including AML1-ETO, CBFA2T3-GLIS2, NUP98-KDM5A, and MLL-AF6 consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis. Mouse bone marrow was lineage depleted and transduced with CIC-NUTM2A, AML1-ETO9a, CBFA2T3-GLIS2 and JAK2 activating mutation, NUP98-KDM5A, or MLL-AF6 retroviral constructs. After 48 hours cells were transplanted into lethally irradiated syngeneic recipients. Bone marrow was collected from moribund mice for RNA sequencing.