Jinjun Dang

Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia 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 (RTK) signaling activation 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.Implications:This study illustrates molecular involvement of phenotypically normal bone marrow in myeloid sarcoma, which has significant implications in clinical care. Further, it extends the definition of CIC-rearrangements to include hematologic malignancies and shows evidence of RTK activation that may be exploited therapeutically in cancer(s) driven by these fusions.

Supplementary Methods and FiguresSupplementary Figure 1. A newborn with isolated myeloid sarcoma.Supplementary Figure 2. Myeloid Sarcoma Histology.Supplementary Figure 3. Bone Marrow.Supplementary Figure 4. Genes Upregulated in CIC-NUTM2A.Supplementary Figure 5. Differential Serial Re-plating Capacity of NUT Family Members.Supplementary Figure 6. Gene Expression Analysis of CIC-NUTM2A Signature.Supplementary Figure 7. Receptor Tyrosine Kinase Signaling.

Supplementary Table 1. Validated Tier 1-3 Mutation CallsSupplementary Table 2. Genes Upregulated in CIC-NUTM2ASupplementary Table 3. CIC-NUTM2A Gene Set Enrichment Analysis in Pediatric Hematologic MalignanciesSupplementary Table 4. ssGSEA for Top Scoring Signaling Pathways in the Clinical DatasetSupplementary Table 5. CRISPR Screen Day 2 vs. Day 17

Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia 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 (RTK) signaling activation 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. Implications: This study illustrates molecular involvement of phenotypically normal bone marrow in myeloid sarcoma, which has significant implications in clinical care. Further, it extends the definition of CIC-rearrangements to include hematologic malignancies and shows evidence of RTK activation that may be exploited therapeutically in cancer(s) driven by these fusions.

Therapy‐related myeloid neoplasms (t‐MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy‐related myelodysplastic syndrome (t‐MDS), therapy‐related myeloproliferative neoplasms (t‐MPN) and therapy‐related acute myeloid leukemia (t‐AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.