Drug target identified for common childhood blood cancer

July 31, 2014

In what is believed to be the largest genetic analysis of what triggers and propels progression of tumor growth in a common childhood blood cancer, researchers at NYU Langone Medical Center report that they have identified a possible new drug target for treating the disease.

T-cell is one of the most common and aggressive childhood . An estimated quarter of the 500 adolescents and young adults diagnosed with the cancer each year in the U.S. fail to achieve remission with standard chemotherapy drugs.

In a cover-story report set to appear in the journal Cell online July 31, the NYU Langone team describes how they used advanced genetic scanning techniques to identify 6,023 so-called long, non-coding strands of RNA, vital chemical cousins of DNA, that were active in the immune system T cells taken from 15 boys and girls with T-cell acute lymphoblastic leukemia, but not active in the healthy T cells in three young people without the disease.

Further analysis found that chemically blocking the action of one of those non-protein-producing RNAs, known as leukemia-induced non-coding activator RNA-1, or LUNAR1 for short, stalled leukemia progression.

Study investigators say LUNAR1 was not singled out from RNA typically used by DNA to make proteins, but rather from among the most prevalent RNA—long chemical strands of translated DNA, previously termed "junk DNA"—which can help transcribe DNA but never fully assemble proteins. They say these long non-coding RNAs are increasingly recognized as key to regulating many cell functions.

Senior study investigator and NYU Langone cancer biologist Iannis Aifantis, PhD, says the study offers preliminary evidence that drugs blocking LUNAR1 could treat T-cell acute lymphoblastic leukemia and a long-sought alternative to chemotherapeutic drugs that kill both cancer and normal cells.

Aifantis, a professor and chair of pathology at the Laura and Isaac Perlmutter Cancer Center at NYU Langone, and an early career scientist at the Howard Hughes Medical Institute, also says LUNAR1 could aid in diagnosing the blood cancer.

"Our study shows that LUNAR1 is highly specific for T-cell acute lymphoblastic leukemia and plays a key role in how this cancer develops," he says, pointing out that overproduction of LUNAR1 was recorded in almost all (90 percent) of leukemia patients tested.

Moreover, Aifantis says, his team's latest findings suggest that development of future cancer therapies based on the underlying genetics of each patient should involve "not just mutations in someone's DNA, but also alterations in the makeup of RNA."

Among the study's other key findings was that while LUNAR1 does not produce cancerous proteins on its own, its production was essential to the cell-to-cell signaling action of another protein, insulin-like growth factor 1 receptor (IGF-1R), already tied to many cancers, including leukemia.

Further laboratory experiments showed that the gene coding for LUNAR1 is near the gene for IGF-1R and located toward the chromosomes' ends, known as telomeres. When activated, LUNAR1's position allows it to chemically loop back and, in turn, bind to and activate IGF-1R.

Researchers zeroed in on LUNAR1 by pinpointing those RNAs that also were active in the NOTCH1 biological pathway. They say the NOTCH1 pathway is common to many cancers, but is especially active in at least half of all people with T-cell acute lymphoblastic leukemia. LUNAR1 stood out right away, they say, as the most highly expressed long, non-coding RNA, of which more than half were newly discovered.

According to Aifantis, his team's research shows that T-cell acute lymphoblastic leukemia, as is the case in many other cancers, could be simply described as a condition of "too much errant signaling." He says in normal T cells, the long, non-coding RNAs such as LUNAR1 are not transcribed, NOTCH1 is inactive, and there is no looping back of LUNAR1 to activate IGF-1R.

To confirm their findings, researchers also transplanted human T cells into mice to prompt , and chemically blocked LUNAR1 in some of the animals. Tumor growth stalled only in those mice whose LUNAR1 was inactivated.

Aifantis says his team's next steps are to develop more effective inhibitors of LUNAR1, preferably something that would precisely target any one or more of its 200-plus component nucleotides.

Explore further: Researchers discover how a mutated protein outwits evolution and fuels leukemia

Related Stories

Researchers discover how a mutated protein outwits evolution and fuels leukemia

June 20, 2013
Scientists have discovered the survival secret to a genetic mutation that stokes leukemia cells, solving an evolutionary riddle and paving the way to a highly targeted therapy for leukemia. In a paper published today in Cell, ...

Key growth factor identified in T cell leukemia

August 1, 2011
Blocking a growth factor receptor cripples cancer growth in a form of T cell leukemia, according to a study published online on August 1 in the Journal of Experimental Medicine.

New culprit discovered in T-cell acute lymphoblastic leukemia

January 12, 2012
A new study published in the journal Nature Medicine by NYU Cancer Institute researchers, shows how the cancer causing gene Notch, in combination with a mutated Polycomb Repressive Complex 2 (PRC2) protein complex, work together ...

Novel target found for chemotherapy-resistant leukemia cells

May 13, 2014
Researchers at Children's Hospital Los Angeles have discovered that by targeting a particular receptor, chemotherapy-resistant cancer cells can be killed in an acute form of childhood leukemia, offering the potential for ...

Study reveals origins of a cancer affecting the blood and bone marrow

May 12, 2011
A new study by the NYU Cancer Institute, an NCI-designated cancer center, sheds light on the origins of myeloid leukemia, a type of blood cancer that affects children and adults. The researchers discovered that novel mutations ...

US regulators fast-track novel leukemia therapy

July 7, 2014
US regulators on Monday put an experimental immunotherapy agent on the fast track to market approval, after 89 percent of leukemia patients in early trials saw their cancers disappear.

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.