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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):178-186
Molecular and phenotypic diversity of CBL- mutated juvenile myelomonocytic leukemia
Anna Hecht,1,2 Julia A. Meyer,1 Astrid Behnert,1 Eric Wong,1 Farid Chehab,3 Adam Olshen,4,5 Aaron Hechmer,4 Catherine Aftandilian,6 Rukhmi Bhat,7 Sung Won Choi,8 Satheesh Chonat,9 Jason E. Farrar,10 Mark Fluchel,11 Haydar Frangoul,12 Jennifer H. Han,13 Edward A. Kolb,14 Dennis J. Kuo,13 Margaret L. MacMillan,15 Luke Maese,16 Kelly W. Maloney,17 Aru Narendran,18 Benjamin Oshrine,19 Kirk R. Schultz,20 Maria L. Sulis,21 David Van Mater,22 Sarah K. Tasian,23 Wolf-Karsten Hofmann,2 Mignon L. Loh1,4 and Elliot Stieglitz1,4
1Department of Pediatrics, Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA; 2Department of Hematology/Oncology, University Hospital Mannheim, Heidelberg University, Heidelberg, Germany; 3Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA; 4Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 5Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA; 6Pediatric Hematology/Oncology, Stanford University, Stanford, CA, USA; 7Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 8Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI. USA; 9Department of Pediatrics, Emory University School of Medicine, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 10Arkansas Children’s Research Institute, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 11University of Utah, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Salt Lake City, UT, USA; 12The Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN, USA; 13Division of Pediatric Hematology-Oncology, University of California San Diego/Rady Children's Hospital San Diego, CA, USA; 14Nemours Center for Cancer and Blood Disorders/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA; 15Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA; 16Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 17Children's Hospital Colorado, Aurora, CO, USA; 18Pediatric Hematology and Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada; 19Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA; 20British Columbia Children’s Hospital and Research Institute, Vancouver, British Columbia, Canada; 21Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 22Department of Pediatrics, Duke University Medical Center, Durham, NC, USA and 23Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ABSTRACT
Mutations in the CBL gene were first identified in adults with var- ious myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uni- parental disomy occurring in affected marrow cells. Here, we systemati- cally studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall out- come. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demon- strate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
Myelomonocytic Leukemia
Correspondence:
ELLIOT STIEGLITZ
elliot.stieglitz@ucsf.edu
Received: August 25, 2020. Accepted: December 21, 2020. Pre-published: December 30, 2020.
https://doi.org/10.3324/haematol.2020.270595 ©2022 Ferrata Storti Foundation
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