VAV1 gene mutations may promote growth of T-cell tumors in laboratory mice

Life is an exquisite orchestration of growth and change, with checks and balances that fine-tune complex entwined interactions, both intrinsic and external.

White blood cells (WBC) are integral to an organism's immune defenses against disease and invasion; unfortunately, these mechanisms may go awry causing uncontrolled increases in dysfunctional cell numbers, resulting in tumor formation.

Now, researchers at the University of Tsukuba have illustrated how mutations in a specific gene called VAV1 may promote tumors involving a type of white blood cell, the T-cell, in experimental mice.

Leukocytes, or WBC, are fundamental to the body's immune function. They include B-lymphocytes that generate antibodies, as well as thymic-lymphocytes or T-cells with diverse immune-related functions, so called because they develop in the thymus gland.

T-cell neoplasms include a mature subtype called peripheral T-cell lymphoma. Studies have shown that VAV1, a gene that participates in T-cell receptor signaling, is altered in several peripheral T-cell lymphoma variants; therefore, the research team sought to elucidate the role of VAV1 mutants in the malignant transformation of T-cells in vivo.

The tumor suppressor gene p53 is called 'guardian of the genome' because it prevents genome mutation. The researchers replicated VAV1 mutations found in human T-cell tumors in both normal ("wild-type") mice and mice lacking p53. Lead author Kota Fukumoto describes their findings:

"No tumors developed in the wild-type mice with VAV1 mutations over a year of observation; whereas immature tumors developed in mice that lacked p53.

Remarkably, mice that both lacked p53 and had mutations in VAV1 developed mature tumors resembling human peripheral T-cell lymphoma, and had poorer prognosis than the mice lacking p53 only."

The team also transplanted tumor cells into mice that lacked a functional thymus. The results suggested that tumor initiation was likely due to mechanisms within the cell itself.

We noted that T-cell tumors with VAV1 mutation showed Myc pathway enrichment, as well as somatic copy number alterations (SCNAs), including at the Myc locus."

Shigeru Chiba, Study Senior Author and Professor, University of Tsukuba

Significantly, Myc, a family of regulator genes and proto-oncogenes, and SCNAs, which cause discrepancies in DNA copies, are both distinct hallmarks of tumor formation.

"Interestingly, pharmaceutical inhibition of the Myc pathway increased overall survival of mice harboring VAV1-mutant tumors," Professor Chiba adds. "Therefore, our methodology and results suggest that the VAV1-mutant expressing mice developed in this study could be a research tool for evaluating therapeutic agents directed against specific T-cell neoplasms."

Source:
Journal reference:

Fukumoto, K., et al. (2020) VAV1 mutations contribute to development of T-cell neoplasms in mice. Blood. doi.org/10.1182/blood.2020006513.

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