Molecular and phenotypic diversity of CBL-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. MaloneyAru Narendran, Benjamin Oshrine, Kirk R. Schultz, Maria L. Sulis, David van Mater, Sarah K. Tasian, Wolf Karsten Hofmann, Mignon L. Loh, Elliot Stieglitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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 uni-parental 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.

Original languageEnglish (US)
Pages (from-to)178-186
Number of pages9
Issue number1
StatePublished - Jan 2022

ASJC Scopus subject areas

  • Hematology


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