Cancer Nexus Blog

While the profound consequences of acute myeloid leukemia (AML) have long been widely recognized, the more recent integration of next-generation sequencing (NGS) into clinical settings has unveiled the dangers posed by mutations in the TP53 tumor suppressor gene. This mutation notably affects patient outcomes and reduces lifespan in patients with AML. This discovery set the stage for a crucial exploration into how this mutation can derail recovery as it sidesteps therapies and curtails remission.

NGS, a powerful tool now commonly used in the clinic, can determine the order of nucleotides in DNA or RNA molecules, uncovering that TP53 mutations occur in approximately 12% of AML patients. In its healthy form, TP53 prevents cells in one’s body from multiplying too quickly. It serves a key role in cell regulation and helps maintain genomic stability by preventing cells with damaged DNAs from replicating. While TP53 mutations are present in various cancers, they are particularly ominous in AML—a type of cancer marked by the excessive production of immature myeloid cells, which are abnormal white blood cells. This form of cancer strikes mostly after age 65, making curative stem cell transplants too toxic for many to withstand. The force of this mutation in AML may be best understood by looking at survival statistics—while those without a TP53 mutation have a 20% chance of surviving five years, individuals with this mutation typically live only six or seven months! This stark contrast underscores the urgency of finding effective interventions against TP53 mutations in AML.

Recognizing the urgent need to address this mutation, Shyam Patel, MD, PhD, and his colleagues are at the forefront of understanding the potent impact of TP53 mutations and devising strategies to mitigate their effects.

The power of the TP53 gene

Dr. Patel and team analyzed 40 patients with either AML or the related blood disorder myelodysplastic syndrome (MDS) and outlined reasons why TP53 mutations are particularly harmful. They explain that TP53 mutations in AML often occur in essential regions of the TP53 gene, such as the DNA-binding domain. When TP53 is healthy, its binding region will attach to specific DNA sequences, regulating the expression of genes involved in crucial cellular processes such as cell cycle control, DNA repair, and apoptosis. If mutation-free, TP53 helps maintain cellular health and prevents the development of abnormal cells. Dr. Patel notes that, when TP53 is mutated, cells may have dysregulated growth kinetics, undergoing abnormal growth patterns and uncontrolled proliferation. These mutant cells may also gain momentum because the TP53 mutation often co-occurs with other gene mutations that control other key functions like RNA splicing and epigenetic regulation.  

There was still much more to learn! In 2020, an extensive study in AML and MDS patients brought further crucial information about TP53 mutations to light. They aren’t all created equally. TP53 multi-hit mutations are the most harmful. These TP53 mutations come in a variety of forms, producing sizable structural changes or affecting numerous cells in the tumors.

The best way to determine prognosis

Traditionally, hematologists use the number of blasts (immature blood cells) to distinguish between MDS and AML. Those with >20% blasts are diagnosed with AML and those with fewer with MDS. Patients with MDS typically live longer, purportedly because they harbor fewer blasts. Now that the importance of the allelic state, or genomic condition, of TP53 is better understood, Dr. Patel and his colleagues investigated whether being diagnosed with AML vs. MDS was the key prognostic determinant or if the allelic state may be more critical.

Using cytogenetics and genomic profiling, they analyzed tumor cells from 76 patients, all of whom exhibited TP53 mutations and were diagnosed with either MDS or AML. “Our results suggest that what’s most important in refining prognosis is the TP53 genomic state of each patient’s unique myeloid neoplasm, rather than classical disease labels of MDS vs. AML,” says Dr. Patel. 

Time is of the essence

With time ticking away for AML patients with TP53 mutations, taking urgent action is important.  Studies indicate that hypomethylating agents (HMAs) are more effective in inducing remission (for patients with TP53-mutant MDS or AML) than chemotherapy. Consequently, prompt assessment for TP53 mutations is crucial. Recognizing that NGS results typically take 14 days to receive, Dr. Patel and his team explored a faster screening method—immunohistochemistry for the p53 protein. This test returns results in just 24 hours and gives early insight into the possibility of TP53 mutations as detected by NGS.

Now, the team will seek ways to make p53 immunohistochemistry the “go-to” analytical tool for detecting TP53 mutations in AML. If patients do carry a TP53 mutation, HMAs can be started immediately, hopefully prolonging life.

In the race against time, silencing the TP53 mutation emerges as the linchpin to enhancing AML outcomes. By understanding the factors that empower these mutations, scientists like Dr. Patel are pioneering novel approaches to target and dethrone them. 

Through ongoing efforts led by Dr. Patel and others, innovative strategies that can transform the landscape of AML treatment by extending life are on the horizon.