Haematologica (Dec 2020)
Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia
- Anna Hecht,
- Julia A. Meyer,
- Astrid Behnert,
- Eric Wong,
- Farid Chehab,
- Adam Olshen,
- Aaron Hechmer,
- Catherine Aftandilian,
- Rukhmi Bhat,
- Sung Won Choi,
- Satheesh Chonat,
- Jason E. Farrar,
- Mark Fluchel,
- Haydar Frangoul,
- Jennifer H. Han,
- Edward A. Kolb,
- Dennis J. Kuo,
- Margaret L. MacMillan,
- Luke Maese,
- Kelly W. Maloney,
- Aru Narendran,
- Benjamin Oshrine,
- Kirk R. Schultz,
- Maria L. Sulis,
- David Van Mater,
- Sarah K. Tasian,
- Wolf-Karsten Hofmann,
- Mignon L. Loh,
- Elliot Stieglitz
Affiliations
- Anna Hecht
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA; Department of Hematology/Oncology, University Hospital Mannheim, Heidelberg University
- Julia A. Meyer
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco
- Astrid Behnert
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco
- Eric Wong
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco
- Farid Chehab
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco
- Adam Olshen
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California
- Aaron Hechmer
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco
- Catherine Aftandilian
- Pediatric Hematology/Oncology, Stanford University
- Rukhmi Bhat
- Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;
- Sung Won Choi
- Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI;
- Satheesh Chonat
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, Georgia
- Jason E. Farrar
- Arkansas Children’s Research Institute, Little Rock, AR; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR;
- Mark Fluchel
- University of Utah, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Salt Lake City, UT;
- Haydar Frangoul
- The Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN;
- Jennifer H. Han
- Division of Pediatric Hematology-Oncology, University of California, San Diego/ Rady Children's Hospital San Diego
- Edward A. Kolb
- Nemours Center for Cancer and Blood Disorders/Alfred I. DuPont Hospital for Children, Wilmington, DE;
- Dennis J. Kuo
- Division of Pediatric Hematology-Oncology, University of California, San Diego/ Rady Children's Hospital San Diego
- Margaret L. MacMillan
- Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN;
- Luke Maese
- Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT;
- Kelly W. Maloney
- Children's Hospital Colorado, Aurora, CO;
- Aru Narendran
- Pediatric Hematology and Oncology, Alberta Children's Hospital, Calgary, Alberta;
- Benjamin Oshrine
- Johns Hopkins All Children’s Hospital, St. Petersburg, FL
- Kirk R. Schultz
- British Columbia Children’s Hospital and Research Institute, Vancouver, British Columbia;
- Maria L. Sulis
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;
- David Van Mater
- Department of Pediatrics, Duke University Medical Center, Durham, NC;
- Sarah K. Tasian
- Division 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;
- Wolf-Karsten Hofmann
- Department of Hematology/Oncology, University Hospital Mannheim, Heidelberg University
- Mignon L. Loh
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco,
- Elliot Stieglitz
- Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco
- DOI
- https://doi.org/10.3324/haematol.2020.270595
- Journal volume & issue
-
Vol. 107,
no. 1
Abstract
Mutations in the CBL gene were first identified in adults with various 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 uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. 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 demonstrate 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.
