Article
Oncology
Laurence C. Cheung, Rebecca de Kraa, Joyce Oommen, Grace-Alyssa Chua, Sajla Singh, Anastasia M. Hughes, Emanuela Ferrari, Jette Ford, Sung K. Chiu, Ronald W. Stam, Ursula R. Kees, Sebastien Malinge, Rishi S. Kotecha
Summary: In vitro efficacy of carfilzomib may not necessarily translate to in vivo benefit, highlighting the importance of in vivo validation before clinical use. While proteasome inhibitors play a crucial role in various hematological malignancies, caution should be exercised before prioritizing carfilzomib for the treatment of KMT2A-rearranged infant ALL in clinical settings.
FRONTIERS IN ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Pauline Schneider, Priscilla Wander, Susan T. C. J. M. Arentsen-Peters, Kirsten S. Vrenken, Dedeke Rockx-Brouwer, Fabienne R. S. Adriaanse, Veerle Hoeve, Irene Paassen, Jarno Drost, Rob Pieters, Ronald W. Stam
Summary: In acute lymphoblastic leukemia (ALL), chromosomal translocations involving the KMT2A gene represent highly unfavorable prognostic factors, and the mutational landscape of KMT2A-rearranged ALL is largely silent, providing limited insights for targeted therapy. However, through CRISPR-Cas9 knock-out screens, the epigenetic regulators ARID4B and MBD3, as well as the receptor kinase BMPR2, were identified as novel vulnerabilities and potential therapeutic targets in KMT2A-rearranged ALL.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Kelly E. Faulk, John A. Kairalla, ZoAnn E. Dreyer, Andrew J. Carroll, Nyla A. Heerema, Meenakshi Devidas, William L. Carroll, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Michael Borowitz, Cindy Wang, Erin Guest, Patrick A. Brown
Summary: We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points in infants with KMT2A-rearranged and KMT2A-germline acute lymphoblastic leukemia. MRD was a strong independent outcome predictor in KMT2A-rearranged infant ALL, but not in KMT2A-germline infant ALL.
PEDIATRIC BLOOD & CANCER
(2023)
Review
Biochemistry & Molecular Biology
Mateusz Gorecki, Ilona Koziol, Agnieszka Kopystecka, Julia Budzynska, Joanna Zawitkowska, Monika Lejman
Summary: The KMT2A gene is a common target for recurrent translocations in various types of leukemia, and its rearrangement has significant prognostic implications.
Article
Genetics & Heredity
Laura N. Eadie, Jacqueline A. Rehn, James Breen, Michael P. Osborn, Sophie Jessop, Charlotte E. J. Downes, Susan L. Heatley, Barbara J. McClure, David T. Yeung, Tamas Revesz, Benjamin Saxon, Deborah L. White
Summary: Chromosomal rearrangements involving the KMT2A gene are common in acute lymphoblastic leukemia (ALL), particularly in infants less than 1 year old. KMT2A-rearranged ALL (KMT2Ar ALL) has a poor prognosis and often co-occurs with other chromosomal abnormalities, including disruption of the IKZF1 gene. This study reports a case of aggressive infant KMT2Ar ALL with rare IKZF1 gene fusions, and highlights the genomic complexity of this disease with the identification of novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1.
Article
Biochemistry & Molecular Biology
Eleonora Khabirova, Laura Jardine, Tim H. H. Coorens, Simone Webb, Taryn D. Treger, Justin Engelbert, Tarryn Porter, Elena Prigmore, Grace Collord, Alice Piapi, Sarah A. Teichmann, Sarah Inglott, Owen Williams, Olaf Heidenreich, Matthew D. Young, Karin Straathof, Simon Bomken, Jack Bartram, Muzlifah Haniffa, Sam Behjati
Summary: This study investigates the developmental state of KMT2A-rearranged infant B-ALL and reveals its unique features compared to other childhood B-ALLs. The research shows that this leukemia harbors hybrid myeloid-lymphoid characteristics and suggests potential targetable antigens for specific cancer treatment.
Article
Hematology
Lisa M. Niswander, Zachary T. Graff, Christopher D. Chien, John A. Chukinas, Christina A. Meadows, Lillie C. Leach, Joseph P. Loftus, M. Eric Kohler, Sarah K. Tasian, Terry J. Fry
Summary: Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 or CD22 have shown promise in treating relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), but antigen loss or downregulation has become a major clinical challenge. In this study, we developed FLT3-targeted CAR T cells and evaluated their efficacy in preclinical models of FLT3-mutant AML and KMT2A-rearranged infant ALL. Our results demonstrate that FLT3-targeted CAR T cells can effectively produce cytokines and kill leukemia cells with minimal cross-reactivity. Bispecific CD19xFLT3-targeted CAR T cells also showed significant activity against KMT2A-rearranged ALL. Overall, our findings suggest that FLT3-targeted CAR T cells could be a highly effective immunotherapeutic strategy for FLT3-mutant AML and KMT2A-rearranged ALL and warrant further investigation and clinical translation.
Article
Biochemistry & Molecular Biology
Clemens Holz, Sandra Lange, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Hugo Murua Escobar, Christian Junghanss, Anna Richter
Summary: Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Recent data indicated that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Masaya Suematsu, Shigeki Yagyu, Hideki Yoshida, Shinya Osone, Yozo Nakazawa, Kanji Sugita, Toshihiko Imamura, Tomoko Iehara
Summary: CD19-specific CAR T cell therapy is used for treating B-cell malignancies. However, relapse caused by antigen-escape has become a major concern. This study found that FLT3-specific CAR T cells showed antitumor efficacy against CD19-negative relapsed cases of KMT2A-r B-ALL, suggesting a promising treatment strategy.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2023)
Article
Hematology
Takayuki Takachi, Tomoyuki Watanabe, Takako Miyamura, Akiko Moriya Saito, Takao Deguchi, Toshinori Hori, Tomomi Yamada, Shigeru Ohmori, Masami Haba, Yuki Aoki, Sae Ishimaru, Shinya Sasaki, Junjiro Ohshima, Akihiro Iguchi, Yoshiyuki Takahashi, Nobuyuki Hyakuna, Atsushi Manabe, Keizo Horibe, Eiichi Ishii, Katsuyoshi Koh, Daisuke Tomizawa
Summary: The use of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) remains controversial due to its potential toxicities, but in the MLL-10 trial, a tailored HSCT strategy with individualized doses of busulfan, etoposide, and cyclophosphamide led to a favorable outcome. Despite achieving good results, the high rate of life-threatening toxicities and risk of late effects may warrant further restriction or elimination of HSCT indications for this patient population in the future.
Article
Oncology
Lin Xiao, Mawar Karsa, Emma Ronca, Angelika Bongers, Angelika Kosciolek, Ali El-Ayoubi, Jezrael L. Revalde, Janith A. Seneviratne, Belamy B. Cheung, Laurence C. Cheung, Rishi S. Kotecha, Andrea Newbold, Stefan Bjelosevic, Greg M. Arndt, Richard B. Lock, Ricky W. Johnstone, Andrei V. Gudkov, Katerina V. Gurova, Michelle Haber, Murray D. Norris, Michelle J. Henderson, Klaartje Somers
Summary: The combination of CBL0137 and the HDAC inhibitor panobinostat shows promising therapeutic potential in KMT2A-rearranged leukemia, enhancing treatment efficacy and extending patient survival.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Pauline Schneider, Nicholas T. Crump, Susan T. C. J. M. Arentsen-Peters, Alastair L. Smith, Rico Hagelaar, Fabienne R. S. Adriaanse, Romy S. Bos, Anja de Jong, Stefan Nierkens, Bianca Koopmans, Thomas A. Milne, Rob Pieters, Ronald W. Stam
Summary: Researchers established acquired resistance to pinometostat in pediatric KMT2A::AFF1+ B-ALL cells, finding that resistant cells became less dependent on DOT1L-mediated H3K79 methylation but still relied on the physical presence of DOT1L, HOXA9, and the KMT2A::AFF1 fusion. Furthermore, these cells lost epigenetic regulation and expression of certain KMT2A-fusion target genes, while other target genes remained unaffected.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2023)
Article
Cell Biology
Anna Richter, Sandra Lange, Clemens Holz, Luisa Brock, Thomas Freitag, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Rico Schwarz, Burkhard Hinz, Hugo Murua Escobar, Christian Junghanss
Summary: Dysregulation of the BCL-2 pathway is a common characteristic of hematological malignancies. The BCL-2 inhibitor venetoclax has shown potential in treating KMT2A-rearranged B-ALL. Venetoclax treatment induces apoptosis, reduces tumor cell counts, and decreases blast frequencies in KMT2A-rearranged B-ALL, but not in other cytogenetic subtypes.
CELL DEATH DISCOVERY
(2022)
Article
Oncology
Koji Nakajima, Hirohito Kubota, Itaru Kato, Kiyotaka Isobe, Hiroo Ueno, Kagehiro Kozuki, Kuniaki Tanaka, Naoko Kawabata, Takashi Mikami, Kosuke Tamefusa, Ritsuo Nishiuchi, Satoshi Saida, Katsutsugu Umeda, Hidefumi Hiramatsu, Souichi Adachi, Junko Takita
Summary: This case report presents a female infant who experienced a lineage switch from KMT2A-MLLT3-rearranged acute monocytic leukemia to KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing revealed two somatic mutations of PAX5 in the relapse sample, which were suggested to be loss of function and potentially driving the lineage switch.
Article
Oncology
Laurence C. Cheung, Carlos Aya-Bonilla, Mark N. Cruickshank, Sung K. Chiu, Vincent Kuek, Denise Anderson, Grace-Alyssa Chua, Sajla Singh, Joyce Oommen, Emanuela Ferrari, Anastasia M. Hughes, Jette Ford, Elena Kunold, Maria C. Hesselman, Frederik Post, Kelly E. Faulk, Erin H. Breese, Erin M. Guest, Patrick A. Brown, Mignon L. Loh, Richard B. Lock, Ursula R. Kees, Rozbeh Jafari, Sebastien Malinge, Rishi S. Kotecha
Summary: In infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL), hypomethylating agents combined with most conventional chemotherapeutic agents showed additive effects in vitro, but antagonistic effects were observed in a subset of samples. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Differential genome-wide DNA methylation, changes in gene expression, and thermal proteome profiling were observed in KMT2A-rearranged infant ALL cell lines treated with azacitidine and decitabine. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity when combined with hypomethylating or conventional chemotherapeutic agents. Addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage, indicating the therapeutic potential of this combination in improving outcomes for infants with KMT2A-rearranged ALL.
Article
Hematology
Emily R. Finch, Monique A. Payton, David A. Jenkins, Xiangjun Cai, Lie Li, Seth E. Karol, Mary Relling, Laura J. Janke
Summary: This study found that using fenofibrate can reduce the occurrence and severity of dexamethasone-induced osteonecrosis in a mouse model, without impacting the survival rate of BCR-ABL+ ALL or the anti-leukemic properties of dexamethasone. This suggests that fenofibrate may be considered for clinical trials as a way to lower triglycerides and reduce osteonecrosis risk in ALL patients.
Article
Hematology
David T. Teachey, Stephen P. Hunger, Mignon L. Loh
Summary: The majority of children and young adults with acute lymphoblastic leukemia (ALL) are cured with contemporary multiagent chemotherapy regimens, which include cycles of chemotherapy over 2-3 years with CNS prophylaxis.
Article
Oncology
Hui Zhang, Anthony Pak-Yin Liu, Meenakshi Devidas, Shawn H. R. Lee, Xueyuan Cao, Deqing Pei, Michael Borowitz, Brent Wood, Julie M. Gastier-Foster, Yunfeng Dai, Elizabeth Raetz, Eric Larsen, Naomi Winick, W. Paul Bowman, Seth Karol, Wenjian Yang, Paul L. Martin, William L. Carroll, Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Cheng Cheng, Stephen P. Hunger, Mary Relling, Mignon L. Loh, Jun J. Yang
Summary: The study showed that the GATA3 gene variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. The findings suggest that inherited genetic variants may play a role in upfront risk stratification in ALL.
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2021)
Article
Pharmacology & Pharmacy
Chuang Jiang, Wenjian Yang, Takaya Moriyama, Chengcheng Liu, Colton Smith, Wentao Yang, Maoxiang Qian, Ziping Li, Morten Tulstrup, Kjeld Schmiegelow, Kristine R. Crews, Hui Zhang, Ching-Hon Pui, William Evans, Mary Relling, Smita Bhatia, Jun J. Yang
Summary: Germline variations in the NT5C2 gene significantly contribute to interpatient variability in thiopurine drug disposition, affecting 6-MP metabolism and leading to differences in drug distribution among patients.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Hematology
Swantje Buchmann, Martin Schrappe, Andre Baruchel, Andrea Biondi, Michael Borowitz, Myriam Campbell, Gunnar Cario, Giovanni Cazzaniga, Gabriele Escherich, Christine J. Harrison, Mats Heyman, Stephen P. Hunger, Csongor Kiss, Hsi-Che Liu, Franco Locatelli, Mignon L. Loh, Atsushi Manabe, Georg Mann, Rob Pieters, Ching-Hon Pui, Susana Rives, Kjeld Schmiegelow, Lewis B. Silverman, Jan Stary, Ajay Vora, Patrick Brown
Summary: Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters defining disease-related events, such as complete remission (CR), treatment failure (TF), and relapse, have significant heterogeneity in their definitions. A consensus definition was established by representatives of major international ALL clinical trial groups, which includes specific criteria for CR, TF, and relapse. These consensus definitions will improve the comparability of outcomes in pediatric ALL trials and promote the development of international collaborative trials.
Article
Hematology
Seth E. Karol, Deqing Pei, Colton A. Smith, Yiwei Liu, Wenjian Yang, Nancy M. Kornegay, John C. Panetta, Kristine R. Crews, Cheng Cheng, Emily R. Finch, Hiroto Inaba, Monika L. Metzger, Jeffrey E. Rubnitz, Raul C. Ribeiro, Tanja A. Gruber, Jun J. Yang, William E. Evans, Sima Jeha, Ching-Hon Pui, Mary Relling
Summary: This study analyzed the dosages of chemotherapy drugs in two acute lymphoblastic leukemia trials. The results showed that, compared to pegaspargase, the native E. coli L-asparaginase formulation had higher dose intensities for some drugs. Additionally, patients with lower dose intensities of asparaginase had higher dose intensities of mercaptopurine. However, lower chemotherapy dose intensity was not associated with relapse.
Article
Oncology
Lindsey E. Montefiori, Sonja Bendig, Zhaohui Gu, Xiaolong Chen, Petri Polonen, Xiaotu Ma, Alex Murison, Andy Zeng, Laura Garcia-Prat, Kirsten Dickerson, Ilaria Iacobucci, Sherif Abdelhamed, Ryan Hiltenbrand, Paul E. Mead, Cyrus M. Mehr, Beisi Xu, Zhongshan Cheng, Ti-Cheng Chang, Tamara Westover, Jing Ma, Anna Stengel, Shunsuke Kimura, Chunxu Qu, Marcus B. Valentine, Marissa Rashkovan, Selina Luger, Mark R. Litzow, Jacob M. Rowe, Monique L. den Boer, Victoria Wang, Jun Yin, Steven M. Kornblau, Stephen P. Hunger, Mignon L. Loh, Ching-Hon Pui, Wenjian Yang, Kristine R. Crews, Kathryn G. Roberts, Jun J. Yang, Mary Relling, William E. Evans, Wendy Stock, Elisabeth M. Paietta, Adolfo A. Ferrando, Jinghui Zhang, Wolfgang Kern, Torsten Haferlach, Gang Wu, John E. Dick, Jeffery M. Klco, Claudia Haferlach, Charles G. Mullighan
Summary: This study identified a subgroup of acute leukemias with ambiguous lineage expressing myeloid, T lymphoid, and stem cell markers, driven by aberrant allele-specific deregulation of the master transcription factor BCL11B. Chromosomal rearrangements and focal amplifications leading to superenhancer generation were identified as mechanisms behind the oncogenic deregulation of BCL11B. This ectopic expression of BCL11B in hematopoietic cells mediated by enhancer hijacking was suggested as an oncogenic driver of human lineage-ambiguous leukemia.
Review
Hematology
Astrid Wintering, Christopher C. Dvorak, Elliot Stieglitz, Mignon L. Loh
Summary: Juvenile myelomonocytic leukemia is a complex disease with diverse clinical outcomes, ranging from spontaneous resolution to transformation to acute myeloid leukemia. Next-generation sequencing allows for more accurate molecular diagnoses, but curative treatment still relies on allogeneic hematopoietic cell transplantation for most patients. Further advances are needed to improve risk stratification algorithms for better management of the disease.
Article
Hematology
Yuhan Yan, Lei Dong, Chao Chen, Kevin D. Bunting, Qianjin Li, Elliot Stieglitz, Mignon L. Loh, Cheng-Kui Qu
Summary: Suppression of normal blood cell development is observed in juvenile myelomonocytic leukemia (JMML), impacting therapeutic outcomes. In a study, the most common mutation found in JMML (Ptpn11(E76K)) was induced specifically in the myeloid lineage, leading to the development of a JMML-like myeloproliferative neoplasm (MPN). Importantly, hematopoietic stem cells (HSCs) in the same bone marrow microenvironment were aberrantly activated and differentiated, resulting in loss of quiescence and exhaustion. Further experiments showed that JMML/MPN cells accelerated differentiation in normal hematopoietic stem/progenitor cells. Excessive production of IL-1 beta by Ptpn11(E76K/+) MPN cells was identified and depletion of the IL-1 beta receptor restored HSC quiescence and rescued them from exhaustion, suggesting IL-1 beta signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
Article
Hematology
Xinjie Xu, Christian N. Paxton, Robert J. Hayashi, Kimberly P. Dunsmore, Stuart S. Winter, Stephen P. Hunger, Naomi J. Winick, William L. Carroll, Mignon L. Loh, Meenakshi Devidas, Thomas G. Gross, Catherine M. Bollard, Sherrie L. Perkins, Rodney R. Miles
Summary: ETP-LLy is a subtype of T-LLy that shares similarities with ETP-ALL but also has distinct genetic features compared to non-ETP T-LLy, indicating it may be a separate entity.
Article
Oncology
Emily R. Finch, Laura J. Janke, Lie Li, Monique A. Payton, David A. Jenkins, Kristine R. Crews, Mary Relling, Seth E. Karol
Summary: Based on the results of our preclinical murine studies, we conclude that dasatinib is unlikely to increase the osteonecrotic effects of dexamethasone in ALL regimens.
PEDIATRIC BLOOD & CANCER
(2022)
Article
Biotechnology & Applied Microbiology
Sarah A. Morris, Kristine R. Crews, Randall T. Hayden, Clifford M. Takemoto, Wenjian Yang, Donald K. Baker, Ulrich Broeckel, Mary Relling, Cyrine E. Haidar
Summary: G6PD deficiency is a common enzyme disorder associated with hemolytic anemia. Clinical G6PD genotyping and activity testing are two commonly used methods that can be used together to determine the G6PD phenotype more accurately.
PHARMACOGENETICS AND GENOMICS
(2022)
Article
Oncology
Elizabeth A. Raetz, Deepa Bhojwani, Meenakshi Devidas, Lia Gore, Karen R. Rabin, Sarah K. Tasian, David T. Teachey, Mignon L. Loh
Summary: Cure rates for acute lymphoblastic leukemia (ALL) have improved over the past decades due to intensified therapy, recognition and treatment of the central nervous system as a sanctuary site, and modern risk stratification. However, recent trials have shown that intensifying traditional chemotherapy does not provide additional benefit, indicating the need for new approaches to cure patients who have been difficult to treat. Differentiating between patients who require intensive or novel therapies and those who can be cured with minimal therapy is crucial for future trials, and new genomic biomarkers and sensitive measures of minimal/measurable residual disease offer opportunities for achieving these goals.
PEDIATRIC BLOOD & CANCER
(2023)
Letter
Oncology
Lauren K. Meyer, Ingold Huang, Benjamin J. Huang, Jong Hee Chung, Anjali Pawar, Michelle L. Hermiston, Mignon L. Loh, Robert S. Ohgami, Roberto Ruiz-Cordero, Parul Bhargava, Amanda E. Marinoff
PEDIATRIC BLOOD & CANCER
(2023)
Article
Oncology
Yoshihiro Gocho, Jingjing Liu, Jianzhong Hu, Wentao Yang, Neekesh V. Dharia, Jingliao Zhang, Hao Shi, Guoqing Du, August John, Ting-Nien Lin, Jeremy Hunt, Xin Huang, Bensheng Ju, Lauren Rowland, Lei Shi, Dylan Maxwell, Brandon Smart, Kristine R. Crews, Wenjian Yang, Kohei Hagiwara, Yingchi Zhang, Kathryn Roberts, Hong Wang, Elias Jabbour, Wendy Stock, Bartholomew Eisfelder, Elisabeth Paietta, Scott Newman, Giovanni Roti, Mark Litzow, John Easton, Jinghui Zhang, Junmin Peng, Hongbo Chi, Stanley Pounds, Mary V. Relling, Hiroto Inaba, Xiaofan Zhu, Steven Kornblau, Ching-Hon Pui, Marina Konopleva, David Teachey, Charles G. Mullighan, Kimberly Stegmaier, William E. Evans, Jiyang Yu, Jun J. Yang
Summary: The study identified LCK and BCL2 signaling as molecular determinants of dasatinib response in T-ALL patients and provided unique opportunities for targeted therapy. High BCL-XL activity, low BCL2 activity and venetoclax resistance were associated with dasatinib-sensitive T-ALL. Discordant sensitivity to dasatinib and venetoclax in T-ALL was correlated with T-cell differentiation and dynamic shift in LCK versus BCL2 activation.
