At the Boldrini Research Center, in Campinas, the group led by Prof. Dr. José Andrés Yunes is dedicated to investigating the biology of acute lymphoblastic leukemia (ALL), the most common childhood cancer. The researchers seek to answer a central question: why are some cancer cells able to resist treatment while others are destroyed?
For this report, we spoke with Prof. Dr. José Andrés Yunes, as well as his students and researchers Ma. Manuella Munuera Rosati, Mikaela Teodoro, Ma. Gabriella de Oliveira Fortes, Maria Luiza Silva Pires, and Ma. Marina Buzatto Gilioli. We also spoke with Prof. Dr. Silvia Brandalise, a pediatrician and founder of the Boldrini Children’s Center.
The Search for New Answers to Childhood Leukemia
For nearly three decades, researcher José Andrés Yunes has dedicated his scientific career to studying leukemias that affect children.
Prof. Yunes holds a degree in Agronomic Engineering from the Federal University of Santa Catarina. He then completed a PhD in Genetics and Molecular Biology at the University of Campinas (Unicamp) in 1997. Yunes also completed postdoctoral research at Unicamp (1997) and at the Dana-Farber Cancer Institute, affiliated with Harvard Medical School, in the United States, between 2001 and 2003. He currently also serves as a collaborating professor at Unicamp, including our Graduate Program in Pharmacology.
Shortly after completing his PhD, Prof. Yunes began his career as a researcher at the Dr. Domingos A. Boldrini Children’s Center for Hematological Research, in Campinas. Today, Prof. Yunes works at the Boldrini Research Center, one of the largest pediatric oncology research centers in Latin America.
The Boldrini Research Center was inaugurated in 2018 to bring cutting-edge scientific research closer to the needs of pediatric oncology. It is one of the few Brazilian centers dedicated exclusively to research into childhood cancer.
Dr. Silvia Brandalise, founder of the Boldrini Children’s Center, describes the creation of this facility: “With the founding of the Boldrini Children’s Center, research activities increased significantly, justifying the need to create the Boldrini Research Center.”
This is because the Boldrini Research Center supports the Boldrini Children’s Center by performing laboratory analyses that help determine the best treatment for children with cancer.
The structure of the Boldrini Research Center is impressive. I, Mia, have already visited several laboratories in Brazil and abroad. I can confidently say that I had never seen a facility as incredible as the Boldrini Research Center.
Within this environment, the work of the Leukemia Biology Laboratory, coordinated by Prof. Yunes, is carried out. The Laboratory’s projects can be said to revolve around one central question: why are some leukemia cells able to survive treatment while others are eliminated by chemotherapy?
To answer this question, different laboratory projects focus on distinct issues: minimal residual disease (leukemic cells that remain in the body after treatment), chemotherapy resistance, the discovery of new therapeutic targets, and the interaction between leukemic cells and the bone marrow microenvironment.
In this article, we will discuss six different projects conducted by Prof. Yunes’s group. But first, we need to understand a little more about acute lymphoblastic leukemia.
What Is Acute Lymphoblastic Leukemia?
To understand what happens in acute lymphoblastic leukemia (ALL), we first need to understand how blood normally works. Blood is made up of different types of cells, each with specific functions.
Red blood cells, for example, are responsible for transporting oxygen throughout the body. Platelets participate in blood clotting, helping to control bleeding. White blood cells play a role in defending the body against infections.
Among the different types of white blood cells are lymphocytes. These cells are essential for what is known as adaptive immunity, a process in which our body recognizes a threat specifically and “remembers” it, allowing for a faster and more efficient response upon subsequent exposure.
For example, when a person is vaccinated against a viral disease, the body begins to produce memory cells against the virus that causes that disease. Thus, if the person comes into contact with that virus in the future, the memory cells will be able to recognize it and organize a rapid defense response.
As mentioned above, lymphocytes are essential for this type of immunity. There are different types of lymphocytes, including B lymphocytes and T lymphocytes, which have different functions.
B lymphocytes can produce antibodies used to specifically identify microorganisms. T lymphocytes, in turn, help coordinate the body’s defense against the microorganism identified by the antibodies.
Both T and B lymphocytes have the same origin: the so-called progenitor cells in the bone marrow. As these progenitor cells develop, they can follow different pathways, eventually becoming T or B lymphocytes.
This is precisely where the story of acute lymphoblastic leukemia (ALL) begins. The disease gets its name because it involves the progenitor cells that give rise to lymphocytes (hence, “lymphoblastic leukemia”) and features rapid proliferation of immature cells (hence, “acute”).
Genetic changes in progenitor cells can cause them to lose their normal mechanisms for controlling cell division. As a result, the cells begin to proliferate uncontrollably.
Prof. Yunes explains: “This cell undergoes a genetic mutation and begins proliferating uncontrollably, taking the place of other normal cells.”
The problem is that the bone marrow functions as a kind of “blood factory.” It is where the cells that circulate throughout the body are continuously produced. When leukemic cells multiply excessively, they begin to occupy the space and resources that would otherwise be used by normal cells.
As a result, the production of healthy blood cells is impaired. A reduction in red blood cells can lead to anemia; a decrease in platelets increases the risk of bleeding; and reduced production of white blood cells can make children more vulnerable to infections.
The Mystery of Relapses
Until the 1960s, a diagnosis of pediatric ALL was practically considered a death sentence. There were no effective treatments.
With the introduction of chemotherapy, doctors observed a major improvement in the treatment of ALL. Initially, chemotherapy involved only one drug. The disease entered remission (it was controlled), but soon returned.
The great revolution came with the introduction of combination chemotherapy (polychemotherapy), combining multiple chemotherapy drugs with different mechanisms of action.
During the first weeks of treatment, around four to five drugs are used together to aggressively fight the disease. Doctors realized that treatment had to be administered at the limit of toxicity. “When the child entered treatment, we couldn’t keep giving them breaks,” explains Prof. Yunes.
Once doctors had improved chemotherapy to increase patient survival after the initial phase, a new challenge emerged. The cancer returned in the brains and spinal cords of many children.
Researchers discovered that this happened because the central nervous system functioned as a “sanctuary” for leukemia. This is because it has the so-called blood-brain barrier, a structure that prevents toxins, as well as several chemotherapy drugs, from entering.
In other words, leukemic cells were able to “hide” from chemotherapy in these regions, allowing them to proliferate. To overcome this, treatment began to include central nervous system prophylaxis, in which medication is administered directly into the cerebrospinal fluid, the fluid that surrounds and protects the brain and spinal cord.
In this way, the medication can reach the central nervous system directly, bypassing filtration by the blood-brain barrier. Thus, leukemic cells hiding in this region can also become targets of chemotherapy.
With the combination of these strategies, survival rates among patients with ALL have improved. At reference centers such as the Boldrini Children’s Center, the cure rate for pediatric ALL exceeds 80% of cases.
What Challenges Remain?
Despite this impressive historic progress, the problem is far from solved. Relapses are still the main challenge. When the disease returns, it means that some leukemic cells managed to escape the effects of the drugs. But how is this possible?
Studies show that some leukemic cells enter a state of “dormancy” (quiescence), temporarily stopping their division. Since many chemotherapy drugs specifically attack cells that are actively dividing, these dormant cells can “go unnoticed.”
These cells remain in the body as minimal residual disease and, when treatment ends, begin to multiply again, causing relapse.
The question is: what is different about these cells that enter a state of “dormancy” compared with other leukemic cells?
You might imagine that these cells acquired mutations that made them stronger. But the truth is that studies show that these cells are genetically identical.
DNA functions like a large recipe book that provides instructions for producing all the proteins a cell needs to perform its functions. But two cells can have exactly the same DNA while “reading” completely different pages of this book.
This means that genetically identical cells can adopt what we call distinct transcriptional states. This results in differences in cell behavior, making some cells slower or dormant.
For this reason, master’s student Manuella Munuera Rosati investigates what is known as transcriptional memory.
Transcriptional memory is the mechanism by which a cell, after being exposed to a stimulus, learns how to respond to that stimulus. In other words, it creates a memory.
According to Manuella, this mechanism may be involved in changes in the transcriptional states of leukemic cells. In this way, they may “learn” how to respond to chemotherapy.
“In many cases, this response occurs more rapidly or intensely (…), allowing the cell to respond more efficiently to a new exposure to stress, contributing to its adaptation and, in some contexts, to its survival.”, explains Manuella.
Manuella’s project seeks to unravel how this transcriptional memory is formed.
In the study, researchers assess how ALL cells that survived chemotherapy respond to 61 different anticancer drugs. This will allow them to evaluate how these cells acquired drug resistance.
In addition, the cells’ transcriptional states will be assessed before and after exposure to chemotherapy drugs. This will also make it possible to determine whether acquired drug resistance is associated with the formation of transcriptional memory.
Unraveling these mechanisms could pave the way for future drugs that target leukemia before it even learns how to defend itself.
The “Little Molecular Robot” That Counts Cell Divisions
Among all the pathways investigated by Prof. Yunes’s group, one in particular seems to have come straight out of a science fiction book. The project led by PhD student Mikaela Teodoro seeks to develop a way to count, cell by cell, how many times a cell has divided since the beginning of its journey.
But why is this so important? Knowing how many times a leukemic cell has divided helps identify where it proliferated rapidly and, more importantly, where it preferred to remain dormant and escape chemotherapy.
To make this possible, the team uses Prime Editing technology. This is an advanced gene-editing technique that works with extreme precision, like an editor of the “text” of DNA. The system will be configured to make small edits to the cell’s DNA each time it divides.
Prof. Yunes summarizes the concept with a metaphor: “It’s like a little molecular robot that you implant into the cell, and it keeps track of how many times that cell has divided. This way, you can find out where the cell becomes dormant and whether this is related to resistance to therapy.”
Therefore, the researchers intend to directly investigate the relationship between the number of cell divisions and the ability of cells to resist chemotherapy treatments.
One Leukemia, Two Subtypes
To an outside observer, ALL may appear to be a single disease. However, it is extremely diverse. Starting with the origin of the affected cells: the disease is divided into B-cell ALL (which accounts for approximately 85% of childhood cases) and T-cell ALL (approximately 15%).
Although less common, T-cell ALL is more aggressive. In addition, differences in cellular origin mean that a treatment effective against B-cell ALL will not necessarily work against T-cell ALL, particularly when conventional chemotherapy fails.
This is the field of research pursued by PhD student Ma. Gabriella de Oliveira Fortes. She summarizes the objective behind her research:
“B and T cells have different transcriptional profiles and tools for surviving treatment. Since conventional drugs are already being used at their maximum tolerated doses, the search for specific targets and new treatment strategies is essential for patients who do not respond to traditional chemotherapy.”
The research maps the molecular characteristics of T-cell ALL samples and cross-references these data with the cells’ responses to 61 anticancer drugs. The goal is to identify molecular markers (genetic characteristics) that indicate which patients are more likely to respond to specific drugs.
This approach opens the door to precision medicine in pediatric oncology: instead of applying a generic treatment to everyone, prior molecular characterization makes it possible to identify specific vulnerabilities in each cancer.
Representing the Diversity of Leukemia
In addition to the main division between B-cell ALL and T-cell ALL, there are dozens of molecular subtypes with their specific genetic alterations, which determine how aggressive the cancer will be and how it will respond to treatment.
This great variety creates a bottleneck for science. Researchers depend on the cell lines available to them. In other words, in their experiments, they can use populations of leukemic cells maintained alive in the laboratory.
The problem is that the cell lines currently available worldwide are limited and do not encompass all known molecular subtypes of ALL.
That is why undergraduate research student Maria Luiza Silva Pires seeks to help fill these gaps through her project.
The study uses samples from the institutional biobank of the Boldrini Children’s Center and attempts to grow them in cell culture. This is far from a simple task. Many of these cells do not multiply in the laboratory. This is a major contradiction, since one of the main characteristics of cancer is uncontrolled growth.
Prof. Yunes comments: “It is surprising how a cell that proliferates so much in a patient does not thrive and dies when you put it in culture.”
As Yunes explains, in the human body, leukemic cells receive constant support from the bone marrow microenvironment. When removed from this “nest” and placed on a plastic plate, most cannot withstand the stress or the absence of the appropriate growth factors.
Establishing new cell lines that can survive in the laboratory without having to be genetically modified would open valuable avenues for research. It would allow researchers to investigate therapeutic approaches that are much more closely aligned with each patient’s reality.
The Environment Also Matters
Speaking of the “nest” of leukemic cells, let’s discuss the importance of the bone marrow. It is a true “blood factory.” The bone marrow microenvironment provides chemical signals, nutrients, and physical support for cell maturation.
In leukemia, the tumor takes advantage of this environment, occupying space and depleting resources that should support the production of healthy blood cells.
Chemotherapy is effective at destroying diseased cells, but it also indiscriminately affects healthy tissues in the bone marrow. As mentioned earlier, chemotherapy attacks cells that divide rapidly. This also occurs in the bone marrow, which continuously produces new blood cells.
This raises a question: would it be possible to selectively stimulate the recovery of our healthy cells lost during chemotherapy so that they could help defeat the disease?
After all, clinical observations and studies conducted by the group itself suggest that patients who are able to restore their population of healthy lymphocytes respond much better to treatment.
The answer to this question may lie in interleukin-7 (IL-7), a molecule essential for lymphopoiesis, that is, the formation and development of new healthy lymphocytes. This is the basis of the project conducted by master’s student Victoria Albeck.
Prof. Yunes explains: “If we stimulate the cells with the cytokine IL-7, we can strengthen the healthy cells and see whether they can gain space and displace the leukemia.”
To make these laboratory tests possible, the team faced a practical obstacle: purchasing commercial IL-7 for animal experiments is extremely expensive. In collaboration with other Unicamp researchers (Dr. Italo E. P. da Silva and Dr. Katlin Massirer), the group produced IL-7 using insect cells as a biological factory.
In addition, they developed a mutant version of the molecule. The genetic modification made it possible to extend the time IL-7 remains in the body.
However, Prof. Yunes is careful to remain realistic when discussing the potential application of IL-7 in patients. The project is still in its early stages, before moving on to animal trials. There is a long experimental and regulatory path ahead before any potential clinical study involving humans.
It Is Not Enough to Fight Leukemia; We Must Also Protect the Body
The search for a cure for childhood leukemia involves a delicate balance. Chemotherapy drugs work by attacking rapidly dividing cells. This characteristic is ideal for fighting cancer, but it also severely affects healthy tissues in the body that have a high rate of renewal, such as the lining of the gastrointestinal tract.
As a result, one of the most painful and debilitating side effects of treatment is intestinal mucositis. Injury and inflammation of the mucosa lining the intestine cause severe pain, frequent diarrhea, and seriously impair nutrient absorption.
In addition, disruption of the intestinal barrier turns the organ into a gateway for bacteria and serious infections. The situation becomes even more dangerous when we remember that ALL patients have weakened immunity because of the disease and its treatment.
In severe cases, gastrointestinal complications force chemotherapy to be temporarily interrupted, reducing the effectiveness of cancer treatment.
This raises a crucial question for science: how can leukemia treatment be made more tolerable and safer without reducing its effectiveness against the tumor?
To address this challenge, PhD student Ma. Marina Buzatto Gilioli is investigating the use of bioactive peptides as a complementary therapy. Bioactive peptides are small fragments of proteins that have immunomodulatory, anti-inflammatory, and tissue-protective properties.
Researcher Marina summarizes the project: “I investigate whether these peptides can protect the intestinal mucosa during chemotherapy, helping the intestine maintain its integrity and recover more quickly from the damage caused by treatment.”
In the experiments, mice receive chemotherapy together with oral supplementation with bioactive peptides or without it. The group carefully evaluates the health of the intestinal mucosa, determining the effectiveness of peptide supplementation.
Prof. Yunes highlights the appeal of this line of research: “It is not that it will directly fight leukemia, but it improves the patient’s quality of life during treatment and reduces infections. It is a promising and practical approach that could, in the future, provide a basis for clinical studies aimed at preventing mucositis in children undergoing treatment.”
What Connects All These Projects?
At first glance, the research paths pursued by Prof. Yunes’s group may seem diverse. And they really are. But ultimately, all these lines of research converge toward the same fundamental goal: to unravel the biology of acute lymphoblastic leukemia in order to make treatments more precise, effective, and safe.
All of these studies are at different stages of what is known as preclinical research. The advancement of medical science follows a long and rigorous journey, with many scientific and regulatory steps before a treatment becomes available. Rigorous testing of efficacy, toxicity, and safety in clinical trials involving patients is required.
It is essential to understand the barriers and requirements at each stage. A promising result observed in cell cultures does not guarantee that the same response will occur in a patient.
This demonstrates that the scientific research conducted by Prof. Andrés Yunes’s group is not simply searching for “a miraculous new drug” for childhood cancer. The work seeks to build a solid body of knowledge by developing a deep understanding of the biology of the disease.
The project featured in this article is funded by FAPESP (grant numbers 24/22071-1, 25/12220-2, 24/03383-2, 24/03384-9, 26/01815-8, 25/17530-0, and 25/03857-7) and by the PRONON program (NUP 25000.211174.2019-45) of the Brazilian Ministry of Health.
This article was produced with support from the São Paulo Research Foundation (FAPESP), Brazil. Grant No. 25/17158-3. The opinions, hypotheses, conclusions, or recommendations expressed in this material are the sole responsibility of the author(s) and do not necessarily reflect the views of FAPESP.
Further Reading:
IL-7 and ALL (doi: 10.1158/0008-5472.CAN-10-3606)
IL-7 receptor mutation and ALL (article 1) (doi: 10.1038/s41467-021-27197-5)
IL-7 receptor mutation and ALL (article 2) (doi: 110.1038/ng.924)
Drug screening for ALL (doi: 10.3389/fonc.2026.1685447)
Mouse model of ALL relapse (doi: 10.3791/68797)
Written by:
Mia Schezaro Ramos
Pharmacist. Ph.D. in Pharmacology. Science journalist, illustrator, trans, Nintendo enthusiast, K-pop fan, and dependent on physical exercise to stay sane.