Mutant Idh2 Cooperates with a NUP98-HOXD13 Fusion to Induce Early Immature Thymocyte Precursor ALL.

Abstract

Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from NUP98-HOXD13 fusion (NHD13) transgenic mice frequently acquire somatic Idh mutations when they transform to acute myeloid leukemia, we generated Idh2R140Q/NHD13 double transgenic mice. Idh2R140Q/NHD13 transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. Idh2R140Q/NHD13 leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for Idh2R140Q/NHD13 DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including KRAS, PTPN11, JAK3, SH2B3, and EZH2 were also found in Idh2R140Q/NHD13 DN1/DN2 T-ALL. In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy. SIGNIFICANCE: T-cell leukemia induced in Idh2R140Q/NUP98-HOXD13 mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.

• Authors: Liat Goldberg, Vijay Negi, Yang Jo Chung, Masahiro Onozawa, Yuelin J Zhu, Robert L Walker, Rachel Pierce, Daxesh P Patel, Kristopher W Krausz, Frank J Gonzalez, Margaret A Goodell, Benjamin A T Rodriguez, Paul S Meltzer, Peter D Aplan
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 19 Pg. 5033-5046 (10 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34321240 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Homeodomain Proteins
• NUP98-HOXA13 fusion protein, human
• Nuclear Pore Complex Proteins
• Oncogene Proteins, Fusion
• IDH2 protein, human
• Isocitrate Dehydrogenase

Topics

• Animals
• Biomarkers, Tumor
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Computational Biology (methods)
• DNA Methylation
• Disease Models, Animal
• Disease Susceptibility
• Gene Expression Profiling
• Heterografts
• Homeodomain Proteins (metabolism)
• Humans
• Immunophenotyping
• Isocitrate Dehydrogenase (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mutation
• Nuclear Pore Complex Proteins (metabolism)
• Oncogene Proteins, Fusion (metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (etiology, metabolism, mortality, pathology)
• Thymocytes (metabolism, pathology)
• Transcriptome