Mutations in CBL occur frequently in juvenile myelomonocytic leukemia

Abstract

Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples. Thirteen of these mutations alter codon Y371. In this report, we also demonstrate that CBL and RAS/PTPN11 mutations were mutually exclusive in these patients. Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML.

Figure 1

Identification of acquired isodisomy of 11q in JMML and CBL mutations. (A) Chromosome 11 loss-of-heterozygosity (LOH) data and copy number heatmaps and plots are shown for 5 representative patients with homozygous CBL mutations, and demonstrate acquired copy-neutral LOH involving CBL for each patient. The region of LOH (blue) in HM1993 is smaller than in the other cases shown but contains the CBL locus. The copy number heatmap generated by dChip is shown where pink represents a diploid copy number, whereas areas of white and red represent loss and gain, respectively. The absence of white and red supports a copy neutral event. This is also represented in the panel on the right where a diploid copy number is represented by the red vertical line, whereas gains and losses are traced in blue; no copy number alterations on chromosome 11 were identified, indicating copy-neutral LOH. (B) Schematic of CBL with expansion of codons in exon 8. Highlighted in red are the residues in exon 8 where missense mutations were identified in JMML and CMML. *Boundary of the linker and RING finger domains. Listed below are the codon numbers. (C) Representative electropherograms from a normal control, the heterozygous mutation from the cord blood sample of HM1854, and the homozygous mutation at diagnosis.