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The spectrum of CBL-mutated JMML
JMML who were not transplanted experienced sponta- neous resolution of their hematologic diseases.8 In our cohort, we observed spontaneous resolution in only three of the 18 non-transplanted CBL-mutated JMML patients. In particular, none of the patients with somatic-only CBL mutations experienced spontaneous resolution, which is consistent with other JMML subtypes harboring somatic Ras pathway mutations. In adults with chronic myelomonocytic leukemia, somatic CBL mutations are found in about 10-15% of cases and are associated with a higher rate of transformation to acute myeloid leukemia and inferior overall outcomes.14-16 Similarly, while germline PTPN11 mutations are associated with Noonan syndrome and a typically self-limited form of JMML,24 patients with somatic PTPN11 mutations experience aggressive leukemia and rarely, if ever, have spontaneous remission.23,25 In our cohort, all five patients with somatic- only CBL mutations were refractory to medium-intensity myeloid-based chemotherapy and required HSCT for definitive disease control. We thus maintain that patients with somatic-only CBL-mutated JMML should not be observed without therapeutic intervention, but instead should be treated with HSCT. Furthermore, somatic-only testing of JMML samples is insufficient for proper identi- fication of these patients, and dedicated germline testing should also be performed in all patients with CBL muta- tions.
Aberrant DNA methylation profiles have shown to be a promising tool for risk stratification in JMML.5,11,23 We therefore assessed the methylome of each patient at diag- nosis. Four of the patients had been assessed for methy- lation in previous methylation studies (UPN1333, UPN2056, UPN2178, UPN2309) that utilized an array- based approach. The current study assessed methylation status using a sequencing-based approach and all four patients were found to have the same methylation desig- nation as in the previous studies. All but two of the 33 patients clustered with the low-methylation group and both of the patients with intermediate methylation relapsed after HSCT. However, methylation analysis was not able to distinguish between patients who experienced spontaneous remission and those with persistent disease. At this time, methylation analysis does not appear to be a biomarker capable of predicting outcome in patients with CBL-mutated JMML, in contrast to other JMML sub- types.
The optimal treatment for patients who require thera- py due to splenomegaly or cytopenias is still unclear. The patients reported in this manuscript were diagnosed between 2006 and 2019. The optimal management of CBL-mutated patients with JMML has evolved over time, and no consensus currently exists given the relatively recent identification of this JMML subtype and the het- erogeneity of its presentation. Several experimental stud- ies have hinted at the potential use of targeted therapies in CBL-mutated disease. Mutant CBL is known to engage LYN/PI3K/AKT and JAK2 proteins, and targeted kinase inhibitors of these signaling pathways have been pro- posed as potential therapeutic strategies.26,27 Preclinical
studies have specifically investigated the SRC/LYN inhibitor dasatinib and have shown decreased sensitivity of CBL-mutant JMML cells to granulocyte-macrophage colony-stimulating factor and increased chemotherapy sensitivity.28,29 Another preclinical study using patient- derived induced pluripotent stem cells with CBL muta- tions reported potential efficacy of JAK2 and PI3K/mTOR signaling inhibition and decreased granulocyte- macrophage colony-stimulating factor hypersensitivity.30 To date, there have been no prospective clinical trials using these agents in JMML. Further research and interna- tional collaboration are warranted to investigate the potential use of targeted therapies in patients with CBL- mutated JMML, as a “watch and wait” approach is likely to be effective in only a minority of patients.
Disclosures
No conflicts of interest to disclose.
Contributions
ES and MLL designed the study. AH, JAM, AB and EW per- formed experiments. AH, JAM, AO and AH analyzed the data and performed statistical tests. FC provided additional germline samples. CA, RB, SWC, SC, JEF, MF, HF, JHH, EAK, DJK, MLM, LM, KWM, AN, BO, KRS, MLS, DVM and SKT pro- vided patients’ samples and clinical data. CA and MLS wrote additional patient vignettes. AH, SKT, WKH, MLL and ES wrote the manuscript. ES supervised the study. All authors read and agreed to the final version of the manuscript.
Acknowledgments
We thank the patients and parents who participated in this study, who made this research possible. We also acknowledge the following physicians who referred patients to our study and without whom this work would not have been possible: Dr. David Becton and Dr. Kimo Stine (Arkansas Children’s Hospital), Dr. Elizabeth Raetz (New York University, Langone), Dr. Paul Shaughnessy (Texas Transplant Institute) and Dr. Alan Ikeda (Children's Specialty Center of Nevada).
Funding
This work was supported by the National Institutes of Health, National Cancer Institute grants 1U54CA196519 (to MLL, ES); 1U01CA232486 (SKT); 1K08CA184418 (SKT); National Institutes of Health, National Heart, Lung, and Blood Institute grant K08HL135434 (ES); the Leukemia Lymphoma Society (MLL, ES); Cookies for Kids Cancer (MLL); Pediatric Cancer Research Foundation (ES); the V Foundation (ES); the UCSF Catalyst Program (ES); the California Cancer League (ES); the Frank A. Campini Foundation (MLL and ES); the Children’s Hospital of Philadelphia Center for Childhood Cancer Research (SKT) and the German Research Foundation HE 7682/1-1 (AH). Next-generation sequencing was supported by the Center for Advanced Technologies at UCSF and the Computational Biology and Informatics group at the UCSF HDFCCC (supported by NCI grant: 5P30CA082103). MLL is the Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair for Pediatric Molecular Oncology at Benioff Children’s Hospital.
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