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Discovery of new leukemia subtypes may lead to targeted therapies, better outcomes
Researchers at St. Jude Children’s Research Hospital identified eight new subtypes of B-cell acute lymphoblastic leukemia, an advance that they hope could lead to improved diagnosis and treatment of high-risk children and adults.
“B-cell ALL has remarkable molecular diversity, which we and others have used to refine classification and drive the development of precision medicines to improve B-cell ALL treatment and outcomes,” Charles Mullighan, MBBS, MD, co-leader of the hematological malignancies program and medical director of the St. Jude Biorepository at St. Jude Children’s Research Hospital, said in a press release. “Part of precision medicine is an accurate molecular diagnosis, which this study provides to more patients.”
Mullighan and colleagues used integrated genomic analysis to define the genomic landscape of B-cell ALL among nearly 2,000 children and adults. The 23 subtypes of B-cell ALL they identified, including eight new subtypes, had distinct genomic and clinical features and outcomes.
HemOnc Today spoke with Mullighan about how this research came about, what he and colleagues found, and the implications of their discoveries.
Question: What prompted this research?
Answer: We had wanted to better understand the genetic basis of ALL for more than a decade. We know that it is multiple diseases, not just one disease. Each disease has its own genetic changes that drive tumor growth. Many patients who lack a known genetic driver for leukemia still fail therapy and relapse, which can be fatal. During the past 9 years, we have been increasing our use of next-generation sequencing technology to better understand the genetics of leukemia in much greater detail. One method is RNA sequencing or transcriptome sequencing. This is particularly useful as it provides multiple levels of information, such as levels of gene expression, detection of rearrangements and fusions of genes, as well as other information, such as sequence mutations.
Q: How did you conduct the study and how long did it take ?
A: This study took us about 3 years to conduct and is one of the largest in this tumor type. This was a collaborative study among faculty investigators with St. Jude Children’s Research Hospital, Children’s Oncology Group, and multiple institutions and cooperative groups that treat adults with ALL. A goal was to examine the genetic basis of ALL across the age spectrum — partly as it has been known for years that outcomes for ALL decrease significantly from adolescence, and the nature of genetic factors responsible for this was not completely understood. The first part of the study was the genetic work and the second was the analysis — both on the genetic level and to associate genetic features with outcome. All samples came from patients treated on uniform protocols, which is important to examine associations between a genetic feature or a subtype of leukemia and subsequent response to treatment.
Q: What did you find?
A: Types of leukemia well-established before this study are often defined by a single fusion of two genes that form a new protein. We identified multiple types in which multiple different genes may be fused to a single gene, and many of these fusions may not be identified by conventional cytogenetic analysis. We also found several examples of subtypes not driven by a gross chromosomal change, but a single-point mutation. The most striking was in the gene known as PAX5, which encodes a protein that is needed for normal B lymphocytes to develop properly. Previously, we considered it to be a usually cooperating, secondary change, but not the initiating driving lesion. In this study, we saw a group with a very distinctive gene expression pattern, and the cases had a single-point mutation in PAX5 P80R. We took this one step further and used genome editing to introduce two different mutations of PAX5 into mice, and we found that the PAX5 P80R mutation was potent in inducing leukemia.
Q: Did the findings surprise you?
A: We were surprised that 50% or more adults did not previously have a known driver lesion. It was striking to see there were four main subtypes that were most frequent among adults, and they were the ones known to be associated with poor outcome. We can now understand why patients with increasing age tend to do worse with current therapy. The flipside was that there are some new subgroups that have been shown in children to have excellent outcomes, and now in adults. This is promising news, as it suggests that there are subsets of adults with ALL who can be treated with less intensive therapy.
Q: Is there anything else that you would like to mention?
A: The implications for diagnosis and predicting outcome are striking and apply to both children and adults. When looking at how we now treat leukemia, we think about the best genetic approaches regardless of age and tailoring therapy accordingly. Our traditional approach — particularly for children — has been to intensify therapy as much as possible to cure everyone. We have reached the ceiling with this approach, and we cannot increase treatment intensity any longer because it is too toxic. We are now using information — such as what we found in this study — to figure out how to treat high-risk patients better, whether with a targeted approach that matches a mutation to a drug or approaching these patients a bit earlier with immunotherapy or targeting the pathway and using a drug discovery approach. – by Jennifer Southall
Reference:
Gu Z, et al. Nat Genet. 2019;doi:10.1038/s41588-018-0315-5.
For more information:
Charles Mullighan, MBBS, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: charles.mullighan@stjude.org.
Disclosure: Mullighan reports no relevant financial disclosures.