A molecular building block of many animal proteins, the amino acid valine plays a key role in cancer growth seen in T-cell acute lymphoblastic leukemia, a new study shows.
Led by researchers at NYU Langone Health, the Department of Pathology and the Laura and Isaac Perlmutter Cancer Center, the study showed that genes involved in valine utilization in cells were more active in cancerous T cells than in normal T cells. .
Blocking these valine-linked genes not only led to a decrease in valine in leukemia blood T cells, but also prevented these tumor cells from growing in the lab. Only 2 percent of the cancerous T cells survived.
Furthermore, experiments suggested that changes (mutations) in the DNA code of the NOTCH1 gene, most commonly seen in patients who develop leukemia, promote cancer growth, in part by increasing valine levels.
The research, published online in the journal Nature on Dec. 22, 2021, involved experiments using human leukemia cells grown in the lab and also transplanted into mice that then develop this cancer, which originates in white blood cells in the bone marrow.
Further experiments showed that feeding the leukemic mice a low-valine diet for three weeks interrupted tumor growth. The diet also reduced circulating blood cancer cells by at least half and in some cases to undetectable levels. In contrast, reintroduction of valine into the diet led to cancer progression.
“Our study confirms that T-cell acute lymphoblastic leukemia is absolutely dependent on a supply of valine and that valine deficiency can slow the progression of this cancer,” said co-lead researcher Palaniraja Thandapani, PhD, a postdoctoral researcher at NYU Grossman School. of Medicine and its Perlmutter Cancer Center.
The research team plans to test next year whether diets low in valine-rich foods, such as meat, fish and beans, are an effective treatment for people with cancer. Low-valine diets are readily available, Thandapani says, because they’re already being used to treat acid imbalances in the body linked to genetic conditions that affect gut metabolism.
Senior study researcher Iannis Aifantis, PhD, says the trial design would likely combine diet therapy with venetoclax, a drug already approved for use in the United States for most other types of leukemia.
The drug combination is important, he says, because such dietary restrictions are unlikely to be sustainable in the long run. This is due to the known potential for muscle loss and brain damage from long-term valine deficiency.
“Our clinical approach involves using low-valine diets to reduce T cell counts in acute lymphoblastic leukemia to levels so low that drugs can effectively slow cancer progression,” said Aifantis, the Hermann M. Biggs Professor and Chair of the Department of Pathology at NYU Grossman and Perlmutter.
Aifantis says many basic cell building blocks, including proteins, nucleotides and fatty acids, are needed for cancer to grow and spread. At least half a dozen other amino acids, especially high levels of lysine, have been implicated in cancers, but their precise role remains unknown. He cautions that nutritional strategies alone for cancer treatment have been tried for decades with little scientific evidence of any benefit. He says more research is needed, including the team’s planned clinical trial, before treatment guidelines can be recommended.
The American Cancer Society estimates that more than 1,500 Americans, mostly children, die each year from T-cell acute lymphoblastic leukemia. Another 5,000 will be newly diagnosed. This type of cancer is responsible for about a quarter of all leukemias.
Reference: “Valine tRNA levels and availability regulate complex I assembly in leukemia” by Palaniraja Thandapani, Andreas Kloetgen, Matthew T. Witkowski, Christina Glytsou, Anna K. Lee, Eric Wang, Jingjing Wang, Sarah E. LeBoeuf, Kleopatra Avrampou , Thales Papagiannakopoulos, Aristotelis Tsirigos and Iannis Aifantis, December 22, 2021, Nature.
DOI: 10.1038/s41586-021-04244-1
Funding support for the study was provided by National Institutes of Health grants P30CA016087, P01 CA229086, and R01 CA228135; the Leukemia & Lymphoma Association; the New York State Department of Health’s NYSTEM program; and the American Association for Cancer Research Incyte Corporation Leukemia Research Fellowship.
Aifantis is a consultant for Foresite Labs, a San Francisco-based healthcare investment company that has financial interests in the development of leukemia therapies. Study co-investigator Aristotelis Tsirigos, PhD, serves as a scientific advisor to Intelligencia.AI in New York City, a software company that applies machine learning to cancer drug development. The terms of these plans are administered in accordance with NYU Langone policies.
In addition to Thandapani, Aifantis and Tsirigos, other researchers from NYU Langone involved in the study are co-investigators Andreas Kloetgen; Matthew Witkowski; and Christina Glytsou; and study co-investigators Anna Lee; Eric Wang, Jingjing Wang; Sarah LeBoeuf; Kleopatra Avrampou; and Thales Papagiannakopoulos.
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