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CBL, Loss of Heterozygosity Is Not a Signature of Juvenile Myelo-Monocytic Leukemia

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CBL, Loss of Heterozygosity Is Not a Signature of Juvenile Myelo-Monocytic Leukemia Letters to the Editor 2404 In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia Leukemia (2013) 27, 2404–2407; doi:10.1038/leu.2013.203 are at increased risk of developing juvenile myelo-monocytic leukemia (JMML), an aggressive myelodysplastic and myeloproliferative neoplasm of early childhood characterized by The CBL gene (11q23.3) encodes an E3 ubiquitin ligase clonal macrophage/monocyte proliferation.3,4 JMML cells are that negatively regulates signaling by promoting degradation of hypersensitive to granulocyte–macrophage colony-stimulating activated tyrosine kinase receptors. In addition, CBL is an adaptor factor consecutively to the activation of the RAS-MAPK signaling protein that positively regulates signal transduction.1 Individuals pathway through the mutation of the following genes: PTPN11, with germline heterozygous CBL mutations present with a NRAS, KRAS, NF1 or CBL. CBL-associated JMML can follow clinically variable condition that can resemble Noonan syndrome an aggressive clinical course or resolve without treatment.4–6 and will be further referred as the ‘CBL syndrome’.2 These patients The current diagnostic criteria for JMML are based on an Table 1. Patients with CBL mutation Hematological Gender Age at Nucleotidic Amino-acid Hematopoietic Germline Pattern of Other RAS- Endogenous Treatment, outcome phenotype diagnosis of change change CBL status CBL status inheritance related growth of (follow up in months) hematological of the CBL mutationsa myeloid disorders mutation progenitors (years) 1 JMML F 1 c.1111 T4C p.Tyr371His Homozygous Heterozygous De novo No Yes Relapse after HSCT (LOF) 2 JMML F 1.1 c.1111 T4C p.Tyr371His Homozygous Heterozygous De novo No Yes HSCT, CR (51 mo) 3 JMML F 2.2 c.1111 T4C p.Tyr371His Homozygous Heterozygous Paternally No Yes HSCT, CR (72 mo) inherited 4 JMML F 1 c.1228-2 A4G Splice site Homozygous Heterozygous De novo No Yes HSCT, CR (80 mo) 5 JMML M 0.5 c.1254 C4G p.Phe418Leu Homozygous Heterozygous Maternally No Yes No treatment, stable inherited disease (72 mo) 6 JMML F 2.1 c.1096 -1delGGb Splice site Heterozygousc Heterozygous De novo No Yes Relapse after HSCT, stable disease (26 mo) 7 JMML F 2.5 c.1111 T4C p.Tyr371His Homozygous Heterozygous De novo No Yes Relapse after HSCT, 2nd HSCT, CR (11 mo) 8 JMML M 4.2 c.1096-1G4C Splice site Heterozygous Wild-type NA NF1 (LOH) Yes JMML progression and second malignancy (rhabdomyosarcoma). Dead 9 JMML M 3.9 c.1150T4C p.Cys384Arg Heterozygous Wild-type NA PTPN11Ala72Val Yes HSCT, CR (21 mo) 10 Splenomegaly F 1.6 c.1258 C4G p.Arg420Gly Homozygous Heterozygous De novo no ND No treatment. Splenomegaly (53 mo) 11 Neutrophilic F 5.7 c.1253 T4C p.Phe418Ser Homozygous Heterozygous Maternally No Yes Mercaptopurine, dermatosis inherited Splenomegaly (34 mo) 12 Lympho-histiocytic M 2.9 c.1141 T4Gb p.Cys381Gly Homozygous Heterozygous De novo No Yes No treatment. syndrome Auto-immune manifestations (44 mo) Abbreviations: CR, complete remission; F, female; HSCT, allogeneic hematopoietic stem cell transplantation; JMML, juvenile myelo-monocytic leukemia; LOF, lost of follow-up; LOH, loss of heterozygosity; M, male; mo, month; NA, not applicable; ND, not determined. aThese mutations were absent from fibroblasts and thus considered as somatically aquired. bNovel mutation (see Figure 1 for details). cIn this patient, microsatellite analysis on serial samples confirmed the absence of LOH after 4 months of evolution of JMML (see Figure 1c). Figure 1. CBL mutations. (a) Sequence electropherograms documenting CBL mutations in the three patients with ‘CBL syndrome’ and atypical immuno-hematological manifestations (patients 10, 11, 12), and in the patient with the novel mutation that remains heterozygous in JMML cells (patient 6). Asterisks indicate heterozygous mutations, black triangles indicate homozygous mutations. Subcloning of mutation c.1096-1delGG (patient 6) in Escherichia coli permitted to sequence separately each allele and confirmed that both deleted bases lied on a single allele. Sequencing of the complete coding sequence of CBL revealed no other mutation in JMML cells (data not shown). Pedigrees of the patients are indicated below. Black boxes: patients with homozygous CBL mutation in peripheral blood; gray boxes: patients with heterozygous CBL mutations in peripheral blood; white boxes: patients with wild-type CBL in peripheral blood. (b) Complementary DNA (cDNA) analysis shows that mutation c.1096-1delGG (patient 6) has the same consequences on splice than mutation c.1096-1G4C (patient 8) previously described.4 Left: reverse transcription PCR using an exon 6 forward primer and an exon 10 reverse primer on RNA and electrophoretic migration in agarose gel. Lane 1: 100–1000 bp size ladder; lane 2: no template control; lane 3: CBL wild-type control; lane 4: patient 8 (c.1096-1G4C); lane 5: patient 6 (c.1096-1delGG). Right: schematic representation of the mRNA variants detected in patients 6 and 8 (D: deletion; ins: insertion). The length of each amplicon is indicated. (c) Analysis of microsatellite markers covering the 11q23 region in patient 6. Loss of heterozygosity (LOH) at CBL locus was assessed by PCR amplification of seven microsatellite markers covering the 11q arm: D11S4206 (11q22.3), D11S4129 (11q22.3), D11S924 (11q22.3), D11S1774 (11q22.3), D11S925 (11q23), D11S934 (11q23-24) and D11S968 (11q25). Fluorescent PCR products were separated by capillary electrophoresis. Allelic sizes are indicated in base pairs (bp) between brackets for each marker. Allelic ratios of JMML cells DNA over germline DNA were calculated as follows: R ¼ [(A1/A2) JMML]/[(A1/A2) Germline]. They were comprised between 0.9 and 1.1, showing no LOH both at diagnosis and 4 months after diagnosis. WT, wild type. Accepted article preview online 4 July 2013; advance online publication, 26 July 2013 Leukemia (2013) 2376 – 2424 & 2013 Macmillan Publishers Limited Letters to the Editor 2405 international consensus that recently incorporated NF1, RAS and protein with defective E3 ligase activity that constitutively PTPN11 mutational status and monosomy 7.7 CBL mutations have activates key RAS effector pathways.4 Importantly, in virtually since been discovered and are also screened for in the workup of all patients described so far, the wild-type CBL allele is lost in patients with suspected JMML.8,9 CBL mutations reported so far leukemic cells and replaced with the mutant allele by acquired are missense mutations or splice site variants clustered in the uniparental isodisomy of the 11q23 chromosomal region leading linker region, and at or near the zinc-coordinating amino acids of to loss of heterozygosity (LOH) of the mutated CBL.4,3,6 Hence, LOH the RING finger domain.1 They all result in the expression of a CBL of the mutated CBL in hematopoietic cells is usually considered as Patient 10 Patient 11 Patient 12 Patient 6 (p.Arg420Gly) (p.Phe418Ser) (p.Cys381Gly) (c.1096 -1delGG) Intron 7 Mutated allele Germline DNA Subcloning (fibroblasts) * into E. coli * * DNA from Wild type allele hematopoietic cells WT 12345612 bp Exon 6 Exon 7 Exon 8 Exon 9 1 Kb 800 bp 600 bp 592 bp Exon 6 Exon 7 ExonExon 88 Exon 9 400 bp 24 bp 200 bp 544 bp Exon 6 Exon 7 ExonExon 88 Exon 9 72 bp 484 bp Exon 6 Exon 7 Exon 9 Exon8 (132 bp) 937 bp Exon 6 Exon 7 Intron 7 Exon 8 Exon 9 Ins intron 7 (321 bp) Size (bp) Germline DNA (fibroblasts) DNA from hematopoietic cells at diagnosis of JMML DNA from hematopoietic cells 4 months after diagnosis D11S4129 D11S968 D11S4206 D11S925 D11S934 D11S1774 D11S924 (114-116) (143-147) (163-167) (175-196) (180-202) (206) (245-249) & 2013 Macmillan Publishers Limited Leukemia (2013) 2376 – 2424 Letters to the Editor 2406 a signature of JMML in patients with ‘CBL syndrome.’ However, to birth. At the age of 5 years, she developed acute febrile date, consequences induced by LOH of CBL mutant proteins neutrophilic dermatosis with multivisceral failure due to neutrophil remain partly unknown. invasion. White blood cell count showed increased circulating CBL mutations were screened in JMML patients of the French neutrophils and monocytes up to 25 Â 109/l and 11 Â 109/l, cohort (n ¼ 102) and in patients referred to our lab with a respectively. Bone marrow aspiration revealed a granular hyper- borderline JMML phenotype. The diagnosis of JMML was based on plasia. A CBL c.1253T4C (p.F418S) homozygous mutation was consensus criteria as described above and included centralized identified in peripheral blood cells and in neutrophils infiltrating a cytomorphological review of bone marrow and blood as well as a cutaneous lesion. An inherited heterozygous mutation was found comprehensive genetic testing by bidirectional Sanger sequen- in her fibroblasts. Treatment with corticosteroid and mercapto- cing of tumoral DNA.5,7 CBL mutations were identified in a total of purine improved her condition and she remains healthy 2 years 12 children. The germline origin of mutations was tested on after with normal white blood cell, although LOH is still detected constitutional DNA (fibroblasts and/or nails). 11q23 LOH was in her hematopoietic cells. explored on tumor cells DNA paired with germline DNA by PCR The third patient (P12) is a young boy who presented with a analysis of microsatellite markers covering the 11q23 region and/ severe hemophagocytic syndrome secondary to an Epstein–Barr or genome-wide single-nucleotide polymorphism (SNP)-array virus infection. Whole-exome sequencing of this patient and his analysis (GeneChip Human SNP-Array 6.0, Affimetrix, Santa Clara, two parents revealed the presence of a de novo c.1141T4G CA, USA).5 In vitro growth of myeloid progenitors from bone (p.C381G) CBL mutation, which was confirmed by Sanger marrow was found positive in all CBL mutated patients who were sequencing.
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