Changes in 3D genetic structure equally important as DNA code mutations in childhood leukemia

By Lois Zoppi, B.A.Mar 23 2020

A study led by researchers at NYU Grossman School of Medicine has found that children with aggressive types of blood cancers are different, not only in the DNA code of their blood cells, but in the twisted protein superstructure that controls access to genes too. This could inform the development of new drugs that target and correct the chromosomal changes in leukemia.

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T-cell acute lymphoblastic leukemia is a variant of acute lymphoblastic leukemia (ALL), which affects the stem cells responsible for generating lymphoid cells. What differentiates T-ALL from ALL is that T-ALL occurs in a particular type of white blood cell called T-lymphocytes, whereas ALL affects B-lymphocytes.

The study, published in Nature Genetics on March 23, 2020, investigated whether T-cell acute lymphoblastic leukemia (T-ALL) worsened depending on structural changes in the layout of chromosomes, and furthered previous work that discovered DNA chains do not exist in tangles of chromosomes, but in organized groups, or ‘neighborhoods’, known as topographically associated domains (TADs).

The arrangement of these chromosomes changes to expose gene-reading machinery to parts of DNA code that are needed to carry out the job each cell is responsible for doing.

In TADs, DNA snippets called enhancers increase or decrease activity in genes, but typically only do this in their own TAD. Within TADs, the DNA is able to fold back on itself in 3D loops, which collects enhancers and promoter DNA that have to interact for lengths of code to be read successfully.

Co-senior author Aristotelis Tsirigos, Ph.D., an associate professor at NYU Langone and Perlmutter, described the changes in DNA looping as “unique” to T-ALL and its related mutations. Looping alterations may, therefore, be different in other types of cancer that also experience mutations.

The researchers compared genetic material from blood samples from eight children, some with advanced leukemia, aged between one and 16, to blood samples of children without cancer. It was discovered that key TAD boundaries were found to be lost in T-ALL, which facilitated the interactions between DNA and enhancers in the wrong chromosome groups, increasing the action of incorrect genes and encouraging the growth and spread of cancer.

This study suggests that the 3D changes in chromosomal structure are as important as mutations in the molecular DNA code, and both of these changes are implicated in cancer’s onset and progression.

Advanced genetic and imaging techniques made the study possible, which included experimental techniques like RNA sequencing and Hi-C, which allows scientists to track genetic activity in cancer cells step by step, revealing the 3D makeup of chromosomes through comparisons with genetic material.

The American Cancer Society estimates that over 1,500 Americans, the majority of them children, die from T-ALL, with this particular type of leukemia accounting for approximately one quarter of all leukemia cases.

Our study is the first to show that the naturally ‘looped’ structure of genetic material in blood cells is changing in T-cell leukemia.

With this in mind, the most effective treatment for this type of leukemia may be a combination of a drug that targets the disease’s cancer-causing genetic mutations and another that counters any changes to chromosomal 3D structure.”

Palaniraja Thandapani, Ph.D., NYU Langone Health and its Perlmutter Cancer Center

According to a study published in Hematology in 2016, T-ALL makes up around 12 to 15 percent of all newly diagnosed acute lymphoblastic leukemia in pediatric patients, but survival rates have been improving and have risen to rates of over 85 percent in modern clinical trials. Despite this, there is a distinct lack of new drugs being developed for children with treatment-resistant cancer.

The two genes that commonly experience changes in childhood leukemia are NOTCH1 and MYC, Iannis Aifantis, Ph.D., the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Langone and Perlmutter, explained, going on to say that drugs currently used to block NOTCH1 and MYC are effective but are not perfect.

Aifantis believes that the explanation for this dip in efficacy could be because of failures in single-drug therapies that do not correct epigenetic alterations characteristic of leukemia after blood cell samples from patients going through therapy were tested.

It is already known that NOTCH1 inhibitors are not effective in many patients, and after running experiments with a drug that did block NOTCH1 activity, Aifantis showed that this blocking mechanism did not extend to block access to exposed MYC TADs.

However, a second experimental drug that targeted epigenetic changes in these particular DNA groups did correct DNA looping in MYC TADs. In these cases, normal chromosomal structure and gene regulation was restored, and as a result MYC action was decreased along with the spread of cancer.

Tsirigos said his research team hopes to describe the changes occurring in chromosomal looping in other types of blood cancer like lymphoma and subtypes of leukemia. He said:

“Once these 3D genetic changes are fully described, we should be able to test existing and new drugs based on their ability to correct any malformations and better predict the chances for patient survival from cancer.”