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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma
Mondira Kundu1, Sheila Compton, Lisa Garrett-Beal
1Genetics and Molecular Biology Branch and Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Chromosomal rearrangements affecting RUNX1 and CBFB are common in acute leukemias. These mutations result in the expression of fusion proteins that act dominant-negatively to suppress the normal function of the Runt-related transcription factor 1 (RUNX)/core binding factor beta (CBFbeta) complexes. In addition, loss-of-function mutations in Runt-related transcription factor 1 (RUNX1) have been identified in sporadic cases of acute myeloid leukemia (AML) and in association with the familial platelet disorder with propensity to develop AML (FPD/AML). In order to examine the hypothesis that decreased gene dosage of RUNX1 may be a critical event in the development of leukemia, we treated chimeric mice generated from Runx1(lacZ/lacZ) embryonic stem (ES) cells that have homozygous disruption of the Runx1 gene with N-ethyl-N-nitrosourea (ENU). We observed an increased incidence of T-lymphoblastic lymphoma in Runx1(lacZ/lacZ) compared with wild-type chimeras and confirmed that the tumors were of ES-cell origin. Our results therefore suggest that deficiency of Runx1 can indeed predispose mice to hematopoietic malignancies.
Insights
Decreased dosage of the RUNX1 gene predisposes mice to hematopoietic malignancies, specifically T-lymphoblastic lymphoma. This suggests RUNX1 deficiency is a critical factor in leukemia development.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Chromosomal rearrangements involving RUNX1 and CBFB are frequent in acute leukemias.
- Mutations create fusion proteins that inhibit normal RUNX1/CBFbeta complex function.
- RUNX1 loss-of-function mutations are found in acute myeloid leukemia (AML) and FPD/AML.
Purpose of the Study:
- To investigate if reduced RUNX1 gene dosage contributes to leukemia development.
- To test the hypothesis that decreased RUNX1 gene dosage is a critical event in leukemogenesis.
Main Methods:
- Generation of chimeric mice from Runx1(lacZ/lacZ) embryonic stem (ES) cells with homozygous Runx1 disruption.
- Treatment of chimeric mice with N-ethyl-N-nitrosourea (ENU) to induce mutations.
- Comparison of tumor incidence between Runx1-deficient and wild-type chimeric mice.
Main Results:
- Runx1(lacZ/lacZ) chimeric mice showed a higher incidence of T-lymphoblastic lymphoma compared to wild-type controls.
- Tumors arising in Runx1-deficient mice were confirmed to be of ES-cell origin.
- These findings support the role of RUNX1 deficiency in hematopoietic malignancies.
Conclusions:
- RUNX1 deficiency can predispose individuals to hematopoietic malignancies.
- Reduced gene dosage of RUNX1 is implicated in the development of leukemia.
- This study provides evidence for RUNX1's role as a tumor suppressor in hematopoiesis.
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