Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia

Abstract

Mutations in the gene CBL 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 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 this disease to be 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 somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Characteristics of RAS pathway mutations in juvenile myelomonocytic leukaemia: a single‐institution study from Korea

“…In one patient, CBL mutations were found in the RING finger domain. 25,26 In addition, we found secondary mutations in SETBP1, JAK3, ASXL1, GATA2, KIT, KDM6A, and BCOR, similar to previous studies. 3,4,[27][28][29][30] Specifically, we detected secondary mutations in SETBP1 and JAK3, which have been described in 5-8% and 11% of JMML cases 3,30 and are associated with poor clinical outcomes.…”

“…NF1 mutations were found in five patients, but none of them showed a syndromic phenotype of NF 1. In one patient, CBL mutations were found in the RING finger domain 25,26 . In addition, we found secondary mutations in SETBP1 , JAK3 , ASXL1 , GATA2 , KIT , KDM6A , and BCOR , similar to previous studies 3,4,27–30 .…”

Current Treatment of Juvenile Myelomonocytic Leukemia

“…Features include impaired growth, facial anomalies, developmental delay, cryptorchidism, autoimmune phenomena, and notably, neurovasculitis [ 26 , 37 ]. However, it is not rare for patients with JMML and CBL germline mutation to display no abnormalities at all [ 26 , 41 , 42 ].…”

“…It is still unclear if the allograft also prevents the later development of symptoms related to autoimmune vasculitis. A recent report highlighted the role of somatic-only CBL inactivation in five patients with a clinical course that required HSCT [ 42 ], again illustrating the need for proper germline analysis in the diagnostic evaluation of JMML.…”

Juvenile myelomonocytic leukemia in the molecular era: a clinician’s guide to diagnosis, risk stratification, and treatment

“…Patients with somatic CBL mutations seem to have a more aggressive phenotype with no cases of spontaneous regression noted to date. 24 Noonan syndrome (NS), another genetic disorder with multiple congenital abnormalities, is caused by germline mutations in PTPN11, SOS1, RAF1, KRAS, and NRAS and predisposes for the development of a transient myeloproliferative disease (MPD) of infancy that typically self-resolves but infrequently requires chemotherapy or even HCT in the case of aggressive disease. 25,26 No patients with NS-associated MPD have been noted to acquire secondary genetic mutations to date; however, cytogenetic abnormalities, with monosomy 7 in particular, have been reported in rare cases.…”