What the study of the mutant gene behind aggressive adult leukaemia can offer for treatment

Certain kinds of mutations in gene TP53, which encodes the p53 tumour suppressor protein, often dubbed the ‘guardian of the genome’, could perhaps be making acute lymphoblastic leukaemia (ALL) one of the hardest cancers to treat, new research has found.

The study, led by Caner Saygin, assistant professor at the University of Chicago Medicine, was recently published in the Blood Cancer Journal, a press release said.

What is ALL?

Acute lymphoblastic leukaemia or acute lymphocytic leukaemia is a type of blood cancer that affects the white blood cells and bone marrow. It is a fast-growing cancer. It is the most common type of paediatric cancer. When it affects adults, it is considered challenging to treat.

A paper published in Cureus in 2024, by Dinesh N. Nalage et al on leukaemia in India, states that leukemia ranked 6th in incidence among all cancers (excluding other neoplasms) from 1990 to 2019, accounting for 4.83% of total cancers. Males are more likely to have leukemia than females, with a 2.24% higher incidence in males. In terms of subtypes, ALL was the number one cause of DALYs and deaths in India in 2019 for both boys and girls aged 0 to 20. While the proportion of ALL declined in both sexes between 1990 and 2019, ALL caused 15.24% of fatalities in men in 2019, while the proportion of mortality in females due to ALL was 10.59% that year.

Understanding TP53

The p53 tumour suppressor protein is stopping for cell division when DNA is damaged, and for initiating repairs. If the damage is irreparable, it is meant to trigger apoptosis, or programmed cell death. But what happens if this does not work as it should? In a healthy cell, TP53 acts as both a brake and an emergency stop button. When DNA gets damaged, this gene either halts the cell to make repairs or orders it to self-destruct before it causes harm. But when the gene mutates, these safety systems fail. The broken cell can keep dividing even while out carrying genetic mistakes, which then pile up until cancer forms.

“In earlier lab work, we found that TP53-mutant ALL cells have increased growth signals and defective cell-death pathways,” Dr. Saygin said, as per the release. “When treated with chemotherapy, these cells accumulate DNA damage, but they don’t die the way they should because the apoptosis pathways are broken, so they persist and eventually cause relapse. That’s why these cancers are so hard to eliminate with standard therapy alone.”

What the study found

The multi-institutional study of 830 adult ALL patients treated at eight academic centres between 2010 and 2024 found that about one in 10 adults diagnosed with ALL had a mutation in TP53. These patients were more likely to relapse and less likely to survive long-term than those without this genetic mutation.

“[This leukemia] is more common in children, so most of what we know comes from paediatric studies. But adult ALL behaves very differently. Adults tend to do worse, and we don’t fully understand why,” Dr. Saygin said. “These collaborations helped us recruit older adults with ALL and uncover the unique biology driving their disease.”

How treatments work

Immunotherapies, which are treatments that boost the body’s own immune system to fight against diseases such as cancer, are used to treat ALL, training the body to spot and destroy leukaemia cells. While immunotherapy works well at first, even in patients with TP53 mutations, the research team found that when TP53-mutant leukemia returned, many of the cancer cells had lost the surface markers that immune drugs target. Without these surface markers the drugs can’t spot the cells, making treatment very challenging, the release said.

Bone marrow transplantation soon after initial remission was one of the few interventions that led to extended survival. Patients who underwent a bone marrow transplant lived about a year longer on average than those who did not. Still, relapse remained common, underscoring how tenacious TP53-mutant clones can be.

What next?

“Right now, we tend to treat adult ALL patients similarly, regardless of their genetics. But our study shows that patients with TP53 mutations need to be treated differently,” Dr. Saygin said. “We need to use immunotherapies early and then move quickly to transplant when patients reach remission. We think transplanting up front, based on genetic risk, could improve long-term survival for these patients.”

“This work reminds us that TP53’s biology depends on cellular context,” noted co-author of the study, Wendy Stock, Anjuli Seth Nayak Professor of Medicine at University of Chicago Medicine as per the release. “In blood cancers, this genetic network may be disrupted by other mechanisms entirely, offering opportunities to restore it indirectly.”

These insights, the researchers hope, could help with designing smarter, more flexible treatments that adjust as the cancer changes.

The Indian scenario

Among the molecular drivers of cancer, TP53 (p53) stands out as the most frequently altered tumor suppressor gene across malignancies. However, its clinical relevance in India remains under-leveraged and insufficiently contextualized within population-specific disease patterns, said Vijayalakshmi Ramshankar, professor and head, department of cancer biology and molecular diagnostics, Cancer Institute, WIA.

In Indian cancers, TP53 alterations are particularly enriched in high-burden malignancies such as oral/head-and-neck cancers, gallbladder cancer, breast cancer, and lung cancer, where they consistently correlate with genomic instability, aggressive tumor biology, and poor clinical outcomes, she noted. “Despite this, TP53 is not routinely integrated into risk stratification frameworks, treatment decision pathways, or national cancer management algorithms, representing a critical translational gap between genomic discovery and clinical application,” Dr. Vijayalakshmi said.

Importantly, TP53 does not function as an isolated biomarker: its true clinical value lies in its role as a contextual modifier of tumour behavior, particularly in the presence of actionable oncogenic drivers, she explained. “For example, in lung cancer, TP53 co-mutations significantly alter therapeutic response and survival outcomes in EGFR-driven disease, underscoring the need for integrated genomic interpretation rather than single-gene reporting. By systematically characterizing and integrating TP53 alterations within Indian cancer cohorts, we can bridge the gap between genomic data and clinical decision-making, ultimately improving risk stratification, therapeutic prioritization, and patient outcomes. “

Published – April 01, 2026 01:31 pm IST