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Chemotherapy Can Set the Stage for Drug-Resistant Leukemia at Relapse

doi: 10.1097/01.COT.0000618196.23121.81
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Chemotherapy has helped make the most common childhood cancer one of the most curable, but researchers have evidence that the treatment may also prime some patients for relapse. Results published in the journal Blood reported that treatment-induced mutations cause drug resistance in some patients whose acute lymphoblastic leukemia (ALL) returns (2019; doi: 10.1182/blood.2019002220).

“Our study reveals the evolution dynamics of pediatric ALL, which suggest for the first time that chemotherapy treatment, particularly thiopurines, can cause mutations that lead to drug resistance in patients,” said study co-corresponding author Jinghui Zhang, PhD, Chair of the St. Jude Children's Research Hospital Department of Computational Biology.

The study involved 103 young ALL patients who relapsed. Most relapsed 9 or more months after diagnosis. The analysis revealed that about 20 percent of these patients had treatment-related mutations at relapse, some associated with drug resistance.

“The mutational signatures are specific and therapy-related, as they are only present in the genomes of relapsed ALL patients but not in other pediatric or adult cancer genomes,” Zhang noted.

The findings underscore the need for less toxic therapies and precision medicine approaches, said co-corresponding author Ching-Hon Pui, MD, Chair of the St. Jude Department of Oncology. Candidates in development include immunotherapies such as CAR T cells and bispecific antibodies.

“This study points to the potential need to individualize therapy when drug-resistant mutations emerge in ALL,” said co-corresponding author Jun J. Yang, PhD, of the St. Jude Departments of Oncology and Pharmaceutical Sciences. The other co-corresponding author is Bin-Bing Zhou, PhD, of Shanghai Children's Medical Center and National Children's Medical Center and the Shanghai Jiao Tong University School of Medicine.

ALL is the most common childhood cancer. With current treatment, more than 90 percent of pediatric patients become long-term survivors. The prognosis is dismal for patients whose leukemia returns. Relapse accounts for 70-80 percent of ALL patient deaths.

While previous studies had identified relapse-specific drug resistance mutations, the origin of those mutations was unclear. Some researchers proposed that ALL relapse was driven by drug-resistant leukemic cells present at diagnosis.

Whole Genome Sequencing Analysis

The children in this study were treated in China. They underwent whole genome sequencing of leukemic cells collected at the diagnosis and relapse, as well as normal DNA. The analysis also included targeted deep sequencing of leukemic cells collected regularly during treatment of 16 patients.

Researchers identified relapse-specific acquired mutations in 12 genes involved in drug response, including FPGS, a novel, relapse-related gene. The analysis also revealed two novel mutational patterns or signatures. Researchers showed thiopurines caused one of the new mutational signatures. Additional research showed the mutations lead to multi-drug resistance.

The timeline of relapse of patients in this study and the presence of relapse-specific mutations in the 12 genes involved in drug response provided insight into the cause.

Most patients, 55 percent, relapsed 9-36 months after diagnosis but before treatment ended. This group had the most relapse-specific mutations in the 12 drug-resistance genes, particularly compared to patients who relapsed earlier. Mathematical modeling, mutational analysis, and other evidence indicated that earlier relapse was likely caused by drug-resistant tumor cells present at diagnosis.

Investigators proposed a two-step process to explain later relapse. The model suggested that relapse occurred when partially drug-resistant tumor cells that were present at diagnosis acquired treatment-related mutations. The now drug-resistant cells divide and eventually cause relapse.

“This suggests drug resistance is not a foregone conclusion,” Yang said. “It may be preventable through changes in the dosage or timing of treatment.” Based on the findings, Pui said screening relapsed patients for drug-resistance mutations may be indicated.

New Approach to Treating Incurable Leukemia in Children Discovered

Acute lymphoblastic leukemia (ALL) is a form of blood cancer that primarily affects children and young people. It involves large quantities of malignant progenitor cells building up in a person's blood instead 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 controlling normal blood development.

Such types of leukemia are often extremely resistant and cannot be cured with intensive chemotherapy or stem cell transplantation. In search of new ways to tackle this problem, a team of scientists from the University of Zurich and the University Children's Hospital Zurich has been scrutinizing the molecular causes of this disorder (Cancer Cell 2019; doi: 10.1016/j.ccell.2019.10.004).

For the purpose of their investigation, the researchers—led by Jean-Pierre Bourquin, MD-PHD, and Beat Bornhauser, PhD—analyzed a protein called TCF3-HLF, which is typically associated with this type of leukemia. This protein does not occur naturally; it is produced through the fusion of two chromosomes and contains elements of what are known as transcription factors, which activate the transcription of certain genes. The analyses revealed that the abnormal protein TCF3-HLF also activates a whole range of genes, but it does so in the wrong context and at the wrong point in the blood development process. This triggers the formation of malignant white blood cells and causes leukemia.

“Our research shows that the abnormal protein binds to almost 500 regulatory elements in the genetic material of the human leukemia cells, activating hundreds of genes by mistake,” explained Yun Huang, PhD, lead author of the study.

The researchers also discovered that the abnormal protein does not act alone. In fact, it gathers more than 100 other proteins around it, which help to activate the genes.

“We investigated the function of the individual proteins in this genetic machinery and used this to identify key elements that could be targeted through therapy,” noted Huang.

He and his colleagues used the CRISPR/Cas9 method, sometimes referred to as a “gene cutter,” to detach the specific parts they had identified from the machinery. As a result, they managed to find eleven critical factors that are crucial to the build-up of malignant abnormal blood cells behind leukemia.

One of the essential components now identified is the protein EP300, a cofactor that boosts gene activation. An experiment with mice indicated that EP300 could be a very promising target for therapy. For this investigation, the researchers used a new kind of substance called A-485, which is known to bind to EP300 and inhibit its activity. When A-485 was administered to mice carrying human leukemia cells, the malignant cells died off.

“It is therefore possible, in principle, to stop the fundamental driving force behind this leukemia directly and thus develop a targeted type of therapy,” stated Bourquin, the research group leader. “The important thing now is to build a fuller picture of what goes wrong so that we can investigate the best possible way to combine specific modes of attack like this.”

Given that other forms of leukemia are caused by similar mechanisms, it may also be possible to identify a common denominator for developing new drugs to combat cancer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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