Acute lymphoblastic leukemia (ALL) is a form of blood cancer that mainly affects children and young people. It involves large amounts of malignant progenitor cells accumulating in the blood in place of healthy white blood cells. This is often caused by a change in genetic material, with two chromosomes fusing together to create new abnormal genes that disrupt the system that controls normal blood development. These types of leukemia are often extremely resistant and cannot be cured with intensive chemotherapy or stem cell transplantation. Scientists have now created a “roadmap” of the genetic mutations found in the most common childhood cancer, acute lymphoblastic leukemia. The St. Jude Children’s Research Hospital study is the first to provide a comprehensive view of the genomics of all subtypes of ALL. The work serves as a fundamental guide for doctors and scientists to understand the development of the disease and improve treatment outcomes.
The research team found that in leukemia normally considered to be low-risk, a single specific genetic rearrangement was associated with a significantly higher risk of relapse. If researchers understand the impact of genetic differences on cancer outcomes, doctors will in the future be able to sequence patients’ cancer before starting treatment. This will allow doctors to tailor treatments for individual patients based on their genetics and the likelihood of responding to different cancer therapies. But before introducing personalized therapies into the clinic, scientists need to map the different mutations that drive the development of leukemia across the landscape of different disease subtypes. The search was unique in that it included 2,574 pediatric ALL patient samples, the largest cohort ever published. By way of comparison, previous studies have typically studied hundreds of samples or fewer.
The research team found that in leukemia the samples normally underwent a combination of whole genome, whole exome or transcriptome sequencing. The researchers compared the sequences to find patterns in the mutations. These models can serve as a roadmap for understanding how leukemia develops and how it can respond to treatment. Overall, the team identified 376 significantly mutated genes that potentially drive cancer development. Seventy of the genes have never been implicated in ALL. Some of the unexpected potential driver mutations are in genes involved in cellular processes such as ubiquitination, SUMOylation or non-protein coding cis-regulation regions. The researchers also found differences in mutations present in ALL subtypes, which can affect clinical care. For example, two of these groups involved specific genetic rearrangements that differed in CEBPA / FLT3 or NFATC4 gene expression.
This observation may have clinical implications, as new FLT3 inhibitors are in clinical trials, suggesting that the CEBPA / FLT3 ALL subtypes may be sensitive to these therapies, but the other subgroup may not. The researchers’ work revealed the sequence of mutation events in many of ALL cases, with potential implications for treatment. In hyperdiploid B-cell ALL (B-ALL), cancer cells have at least five more chromosomes than normal (46 in humans). A longstanding question has been the relative timing of chromosomal gains and other mutations in the development of hyperdiploid ALL. Understanding this process would provide important information on how leukemia develops. The researchers then traced the order of events leading to hyperdiploid ALL using computational modeling of the mutation sequence and chromosomal gain data.
This showed that in most cases of hyperdiploid B-ALL, chromosomal gains seem to occur early and all at once, a kind of chromosomal “big bang”. Hence, precancerous cells get more mutations, partly due to ultraviolet (UV) light-induced DNA damage. The finding shows that UV damage contributes to the development of ALL, a previously controversial notion. In fact, curative exposure to sunlight to take advantage of UV rays is notoriously associated with the personal treatment of psoriasis. UV radiation reduces the severity of the disease because it causes functional damage to the lymphocytes, suppressing the immune response. But considering these findings, it is therefore possible that even exaggerated sun exposure over time can contribute to the onset of leukemia, if the damaged lymphocytes do not die but remain carriers of potentially oncogenic mutations.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Brady SW, Roberts KG et al. Nat Genet. 2022 Sep 1.
Newman S et al. Cancer Discov. 2021; 11(12):3008-27.
Brady SW et al. Blood. 2020 Nov 5; 136(19):2235-2237.
Tottone L et al., Palermo R. Front Oncol. 2019; 9:198.
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Dott. Gianfrancesco Cormaci
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