Shunsuke Kimura, PhD, Hiroto Inaba, MD, PhD, and Charles Mullighan, MD, MBBS, collaborated on research to better understand γδ T-ALL.
Understanding the molecular characteristics of cancer that impact patient outcomes is essential to identify novel treatment strategies for the most intractable pediatric malignancies. Many of these diseases are difficult to study, however, due to the small number of patients diagnosed each year. Investigators from St. Jude Children’s Research Hospital and an international collaborative group of over 50 researchers joined forces to understand better a type of rare childhood leukemia – gamma delta T-cell acute lymphoblastic leukemia (γδ T-ALL). The findings revealed a high-risk subtype of the disease and a genomic vulnerability that may be targeted by a class of existing drugs. The study was published today in Cancer Discovery, a journal of the American Association for Cancer Research.
Acute lymphoblastic leukemia (ALL) represents approximately 30% of all childhood cancers. T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood ALL, and 10-15% of T-ALL cases express the gamma delta T-cell receptor, termed γδ T-ALL. Investigators at St. Jude previously observed poor clinical outcomes among patients diagnosed with γδ T-ALL, however, the disease’s rarity led to small numbers of patient samples that made studying the underlying biology of the disease challenging.
“This is a great example of a clinical question that needed to be answered through collaboration,” said co-corresponding author Hiroto Inaba, MD, PhD, St. Jude Department of Oncology, Division of Leukemia/Lymphoma interim director. “We needed a large collaborative effort to really understand the genetics and get at what is happening in these cases to figure out how to potentially treat them.”
The St. Jude investigators turned to the global pediatric leukemia community, identifying 13 clinical study groups investigating T-ALL from which the team could gather data on the γδ T-ALL cases. Altogether, they identified 200 children with γδ T-ALL, making this the largest cohort of the disease yet reported. With this cohort, the investigators were able to dive into the genomic landscape of the disease, revealing the molecular characteristics that distinguish a high-risk subtype of γδ T-ALL, and a potential way to treat it.
Age and genetic mutations distinguish high-risk γδ T-ALL
T-ALL is rare in infants and very young children. However, the investigators found that when γδ T-ALL does occur in children under three years old, the disease has worse outcomes. In addition to age, the researchers also found that the cases with the worst outcomes had a high occurrence of genetic alterations that resulted in both activation of LMO2, a gene commonly altered in other types of T-ALL, and inactivation of STAG2, a gene more commonly altered in acute myeloid leukemia and solid tumors.
“We didn’t know going into this study if we would find a single subtype or a single genetic change that would define this γδ T-ALL subtype,” said co-corresponding author Charles Mullighan, MD, MBBS, St. Jude Department of Pathology. “But we found quite striking enrichment of STAG2/LMO2 alterations and were able to dig into that to understand the rearrangement and the impact it was having on the biology of the disease.”
Using patient samples, xenograft models and genetically manipulated cell lines, the researchers showed that inactivation of STAG2 has a profound effect on the organization of chromatin (imagine a spool around which DNA is wound). STAG2 inactivation disrupts gene expression associated with the differentiation (maturation) of T-cells by altering enhancer-promoter looping (the way that instructions about which genes should be expressed are conveyed).
“Chromosomal rearrangement between two genes is a hallmark of leukemia, but what we found was different because what this alteration does is switch STAG2 off, taking the STAG2 promoter and moving it proximal to LMO2, switching it on,” explained Mullighan. “This dual mechanism is unusual and provides insight into the biological consequences of these changes to explain what is going on at the genomic level in this rare cancer.”
“What this work really underscores is that when patients with T-ALL arrive in the clinic, you need to identify those with this γδ T-ALL subtype,” added Mullighan. “Recognizing this subtype so that treatment can be tailored accordingly is incredibly important for patients.”
A potential treatment strategy emerges
In addition to gaining a more complete picture of the underlying genomics fueling the poor outcomes observed clinically in γδ T-ALL, the study also highlighted a potential treatment strategy: Poly(ADP-ribose) polymerase (PARP) inhibitors.
DNA is damaged throughout one’s life, so the human body has built-in DNA repair mechanisms. However, many cancers hijack these DNA repair pathways to make the body more hospitable to cancer cells and their irregular DNA. PARP is part of one of these DNA repair pathways, and existing drugs to inhibit it have shown success in several cancers. The researchers conducted drug screening and pharmacogenomic analyses to identify therapeutics with the potential to treat γδ T-ALL. PARP inhibitors emerged as the compounds with the most promise.
“This is very exciting to identify a potential targeted therapy for these patients who have typically poor outcomes,” said Inaba. “Many cases of ALL are curable, but some are not yet and that’s where we need to focus. Targeted therapies can provide a new option and may even be able to reduce the side effects or late effects of treatment by targeting the cancer cells more directly.”
“This story is not the end,” added Inaba. "By having these genomic and clinical datasets we will continue to search for better treatments.”
Authors and funding
The study’s first author is Shunsuke Kimura of St. Jude. Other authors include Andishe Attarbaschi, St. Anna Children’s Hospital and St. Anna Children’s Cancer Research Institute; Barbara Buldini, University of Padova and Istituto di Ricerca Pediatrica (IRP)-Citta della Speranza (Italy); Kenneth Caldwell, Gilead Sciences; John Kim Choi, University of Alabama at Birmingham; Valentino Conter, Fondazione IRCCS San Gerardo dei Tintori (Italy); Hester de Groot-Kruseman, Jules Meijerink, and Rob Pieters, Princess Maxima Center for Pediatric Oncology (Netherlands); Takao Deguchi, National Center for Child Health and Development; Mariko Eguchi, Ehime University (Japan); Hannah Elisa Muhle, and Gabriele Escherich, University Medical Center Hamburg-Eppendorf (Germany); Sarah Elitzur, Schneider Children’s Medical Center and Faculty of Medicine (Israel); Keizo Horibe, National Hospital Organization Nagoya Medical Center; Toshihiko Imamura, Kyoto Prefectural University of Medicine; Motohiro Kato, Tokyo University; Kean Hui Chiew, and Allen EJ Yeoh, National University of Singapore; Michal Kicinski, EORTC Headquarters (Belgium); Stefan Kohrer, Labdia Labordiagnostik GmbH (Austria); Steven Kornblau, University of Texas MD Anderson Cancer Center; Rishi Kotecha, Perth Children’s Hospital, Telethon Kids Cancer Center, and Curtin University (Australia); Chi-Kong Li, The Chinese University of Hong Kong; Franco Locatelli, Catholic University of the Sacred Heart (Italy); Selina Luger, Abramson Cancer Center University of Pennsylvania; Elisabeth Paietta, Montefiore Medical Center; Atsushi Manabe, Hokkaido University Graduate School of Medicine (Japan); Hanne Vibeke Marquart, Rigshospitalet, University of Copenhagen (Denmark); Riccardo Masetti, IRCCS Azienda Ospedaliero Universitaria di Bologna (Italy); Melissa Maybury, University of Queensland (Australia); Pauline Mazilier, HUB-HUDERF (Belgium); Takako Miyamura, Osaka University Graduate School of Medicine (Japan); Andrew Moore, University of Queensland and Children’s Health Queensland Hospital and Health Service (Australia); Koichi Oshima, Saitama Children’s Medical Center; Katarzyna Pawinska-Wasikowska and Szymon Skoczen, Jagiellonian University Medical College (Poland); Michaela Reiterova, Charles University (Czech Republic); Michael Svaton, St. Anna Children’s Cancer Research Institute, Charles University, and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences; Jan Stary, Charles University and University Hospital Motol (Czech Republic); Jacob Rowe, Shaare Zedek Medical Center (Israel); Atsushi Sato, Miyagi Children’s Hospital; Kjeld Schmiegelow, Rigshospitalet University Hospital (Denmark); Martin Schrappe, University Hospital Schleswig-Holstein (Germany); Shuhong Shen and Yanjing Tang, Shanghai Children’s Medical Center (China); Orietta Spinelli, ASST-Papa Giovanni XXIII Hospital (Italy); Masatoshi Takagi, Tokyo Medical and Dental University (Japan); Junko Takita, Graduate School of Medicine Kyoto University (Japan); Tiffaney Vincent, Children’s Hospital of Philadelphia; Martin Zimmermann, Medical School Hannover (Germany); and Chun Shik Park, Lindsey Montefiori, Ilaria Iacobucci, Petri Polonen, Qingsong Gao, Yunchao Chang, Chelsey Chen, Cheng Cheng, Burgess Freeman, Zhaohui Gu, Katie Han, Zhongshan Cheng, Sima Jeha, Tanya Khan, Yen-Chun Liu, Chunxu Qu, Kathryn Roberts, Elizabeth Arnold, Sharnise Mitchell, Mollie Prater, Shondra Pruett-Miller, Noemi Reyes, Anthony Brown, Kristine Crews, Jun J. Yang, Yinmei Zhou, Ching-Hon Pui, all of St. Jude.
The study was supported by grants from the National Institutes of Health (R35CA197695, P50CA021765, R03CA256550, F325F32CA254140, U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866, and U24CA196173), the Henry Schueler 41&9 Foundation, a St. Baldrick’s Foundation Robert J. Arceci Innovation Award, Gabriella Miller Kids First award (X01HD100702), a Garwood Postdoctoral Fellowship of St. Jude, the Ministry of Health of the Czech Republic (NU23J-03-00026), the Charles University Research Center (UNCE/24/MED/003), and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.