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FBXW7 mutation in adult T-cell and B-cell acute lymphocytic leukemias
Jee Hoon Song1, Nikolai Schnittke, April Zaat
1Department of Medicine, UCLA/Cedars-Sinai Research Institute, 110 George Burns Drive, Davis 5016, Los Angeles, CA 90034, USA.
Abstract:
The FBXW7 (also known as AGO, hCDC4, FBW7 and SEL-10) gene encodes a subunit of an ubiquitin protein ligase which regulates levels of cyclin E, NOTCH and other proteins. Engineered FBXW7 null cells display cell cycle and chromosome stability defects. Mutations of FBXW7 have been found in human colorectal, ovarian, endometrial tumors and T-cell acute lymphocytic leukemias. Prompted by these findings we have examined acute myeloid leukemia, non-Hodgkin's lymphoma, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia and adult T-cell leukemia DNA for mutations of the FBXW7 gene. Mutations were detected by PCR-SSCP of all coding exons of the three isoforms of FBXW7, shifted bands were direct sequenced. As expected, mutations were found in T-cell acute lymphocytic leukemias. However mutations of FBXW7 were also found in four of 118 B-cell acute lymphocytic leukemias and one of 24 adult T-cell leukemia samples. The nucleotide changes consisted of an insertion, resulting in a frameshift mutation, and missense mutations of highly conserved residues. All mutations affected the FBXW7 target interacting domain. These observations suggest that disruption of FBXW7 has a role in several forms of lymphocytic leukemias and not exclusively T-cell acute lymphocytic leukemia.
Insights
Mutations in the FBXW7 gene, which regulates cell proteins, were found in B-cell acute lymphocytic leukemia and adult T-cell leukemia. These FBXW7 gene disruptions suggest a role in various lymphocytic leukemias beyond T-cell acute lymphocytic leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The FBXW7 gene encodes a ubiquitin ligase subunit regulating key proteins like cyclin E and NOTCH.
- FBXW7 mutations are implicated in various cancers, including colorectal, ovarian, endometrial tumors, and T-cell acute lymphocytic leukemia.
- Engineered FBXW7-deficient cells exhibit cell cycle and chromosome instability.
Purpose of the Study:
- To investigate FBXW7 gene mutations in acute myeloid leukemia, non-Hodgkin's lymphoma, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia, and adult T-cell leukemia.
- To determine if FBXW7 mutations are present in leukemias beyond T-cell acute lymphocytic leukemia.
Main Methods:
- Screening of all coding exons of the three FBXW7 isoforms using PCR-SSCP.
- Direct sequencing of PCR products with shifted bands to identify mutations.
- Analysis of DNA from various leukemia patient samples.
Main Results:
- FBXW7 mutations were confirmed in T-cell acute lymphocytic leukemias as expected.
- Mutations were also identified in 4 out of 118 B-cell acute lymphocytic leukemia samples.
- One mutation was found in 1 out of 24 adult T-cell leukemia samples, including frameshift and missense mutations affecting the target-interacting domain.
Conclusions:
- FBXW7 gene disruption plays a role in B-cell acute lymphocytic leukemia and adult T-cell leukemia.
- The findings indicate that FBXW7 mutations are involved in a broader spectrum of lymphocytic leukemias than previously recognized.
- These mutations may contribute to leukemogenesis by affecting critical protein regulation.
