CBL Mutations In Pediatric Acute Myelogenous Leukemia Are a Rare Event, a Report From the Children's Oncology Group.

The CBL gene encodes a ubiquitin ligase that targets multiple activated tyrosine kinases for degradation. Analysis of several series of patients with myeloid malignancies demonstrated mutations in the RING finger domain and linker domains encoded by exons 8 and 9 of the CBL gene. Loh, et al (Blood, 114:1859-63, 2009) analyzed 159 samples from pediatric patients with juvenile myelomonocytic leukemia (JMML) for mutations in those exons. They found CBL mutations in 27 (17%) of the samples. We sought to determine the prevalence of mutations in CBL exons 8 and 9 in pediatric patients with de novo acute myeloid leukemia (AML). We analyzed 290 samples from pediatric patients treated on the Children's Oncology Group study AAML03P1. DNA was isolated from diagnostic bone marrow samples. Exons 8 and 9 of the CBL gene were amplified by PCR and then sequenced for mutational analysis. Five of 290 (1.7%) patients had CBL exon 8 or 9 mutations (Table 1). Patient 1 had a heterozygous splice site mutation (1096 –1G>T). Patient 2 had a homozygous missense mutation (C384S). Splice-site mutations and mutations of the C384 residue were also seen in JMML. Two patients had synonymous heterozygous mutations (P433P and I429I), and 3 patients had heterozygous insertions and deletions. Patient 3 had a 121-bp deletion that included 66 base pairs at the 3’ end of exon 8 and the first 55 base pairs of intron 8. Loh, et al (Blood, 2009) also found a similar 99-bp deletion in JMML. Patient 4 had a 3-bp duplication in exon 9 (1382-1383ins TGA) with TGA repeated 7 times; TGA is repeated 6 times in wild-type cells. Patient 5 had a complex insertion and deletion: 73 base pairs (31 base pairs in intron 7 and 42 base pairs at the 5’ end of exon 8) were deleted, and 26 base pairs were inserted at the site of the deletion. We examined the clinical features and other genetic abnormalities among these 5 patients with CBL mutations. All of the patients had an abnormal karyotype, including monosomy 7, t(8;21), t(9;11), or inv(16). We tested FLT3 status (internal tandem duplications and point mutations), CEBPA, and NPM1. Patient 5 had a FLT3 point mutation. We conclude that CBL mutations in the RING finger and linker domains are rare in pediatric de novo AML compared to their prevalence in JMML.

No relevant conflicts of interest to declare.