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Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia

Ras proteins are molecular switches that cycle between inactive GDP-bound and active GTP-bound states.1 Growth factors activate Ras by recruiting the nucleotide exchange factor Son of Sevenless (SOS1) to the plasma membrane.2, 3 Ras signaling has profound consequences for the cell and unregulated Ras activation is a hallmark of cancer. Germline mutations of genes activating this pathway can also cause developmental disorders, such as Noonan (PTPN11, KRAS), Costello (HRAS), and cardio-facio-cutaneous syndromes (KRAS, BRAF, MEK1/2), as well as neurofibromatosis type 1 (NF1).1

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder (MPD) characterized by leukocytosis, tissue infiltration by malignant cells, and in vitro hypersensitivity of myeloid progenitors to granulocyte–macrophage colony stimulating factor.4, 5 The incidence of JMML is increased in children with neurofibromatosis type 1 (NF1).5 NF1, which is diagnosed in 11% of all JMML cases, is an autosomal dominant cancer predisposition syndrome caused by mutations of NF1 coding for neurofibromin, a GTPase activating protein (GAP) for Ras.5 JMML cells from patients with NF1 show biallelic NF1 inactivation and elevated Ras·GTP levels.5 Approximately 25% of JMML cases have somatic RAS mutations, which are identified in patients who do not have NF1.5 These data and studies in mouse models underscore a crucial role of hyperactive Ras in the pathogenesis of JMML.5

Germline PTPN11 mutations cause 50% of cases of Noonan syndrome (NS; MIM 163950),5 an autosomal dominant disorder characterized by short stature, distinct facial features, and cardiac defects. PTPN11 encodes SHP-2, a non-receptor tyrosine phosphatase (PTPase) that regulates multiple responses including proliferation, differentiation, and migration.6 SHP-2 is a positive regulator in signal transduction, which is mediated, in part, through the Ras pathway.6 Infants with NS are predisposed to MPD resembling JMML (NS/JMML).7 Interestingly, specific germline PTPN11 mutations were identified in most cases of NS/JMML and somatic mutations, largely restricted to patients without clinical NF1 or mutations in RAS, occur in 35% of JMML cases.7

KRAS germline mutations are a rare cause of NS.1, 8 These mutations encode specific gain-of-function alleles that have been in part studied in detail and shown to exhibit effects that are less pronounced than those exhibited by cancer associated mutant K-RasG12D, thus offering an explanation why these germline mutations are tolerated during embryonic development.8 Taken together, there is a close connection between JMML and NS, both being model diseases for somatic and germline events leading to increased signaling through the Ras pathway, respectively (Figure 1). Nevertheless, in 25% of JMML cases and 50% of NS cases, no mutations are identified, suggesting that mutations in other genes of this pathway may be involved in human disease.

Figure 1

Simplified Ras-signaling pathway. Proteins involved in the pathogenesis of Noonan syndrome (germline mutations of PTPN11 (SHP-2), KRAS or SOS1) or JMML (biallelic inactivation of NF1 or somatic mutations of PTPN11, KRAS or NRAS) are indicated in black.

After the recent discovery of SOS1 germline mutations in 10% of cases of NS (MZ, paper in preparation),2, 3 we screened JMML specimens from patients without NF1 that lacked mutations in PTPN11 or RAS for SOS1 mutations. Diagnostic blood or bone marrow cells from patients with NS/JMML (n=5) or JMML (n=44) enrolled in the EWOG-MDS study or from patients diagnosed in the US were collected and analyzed with informed consent and Institutional Review Board-approved protocols. The entire coding sequence of SOS1 was sequenced in 22 samples. The remaining 27 JMML specimens were screened for mutations in mutational hotspots of NS including exons 3, 6, 7, 8, 10, 11, 12, 13, 14, 16 and 19 (MZ, manuscript in preparation).2, 3 No pathologic mutations were detected. However, we identified a known polymorphism, c.1964 C → T (P655L), in three JMML specimens.

We conclude that SOS1 does not act as a proto-oncogene in JMML, which is in contrast to the previous two NS genes, PTPN11 and KRAS. Further candidate gene approaches will be necessary to identify JMML genes mutated in 25% of cases without a clinical diagnosis of NF1 or mutations in PTPN11 or RAS. Besides SOS1, we have recently screened most exons of SHC1, GRB2, and GAB1 and not identified any mutations in 15 patients with JMML and two patients with NS/JMML. Additionally, no mutations have been identified in MEK1 (exons 2 and 3) or MEK2 (exon 2) in seven patients with isolated JMML and two patients with NS/JMML.


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This work was supported by US Public Health Service Grants R37CA49152 and R01CA11945 (KS and BN) from the National Institutes of Health. The authors wish to thank all of the patients, families, and referring physicians who contributed samples to the investigators. We thank Angelika Diem and Marco Teller for their excellent technical assistance. We are grateful to Dr Mwe Mwe Chao for critical comments.

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Correspondence to C P Kratz.

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Kratz, C., Niemeyer, C., Thomas, C. et al. Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia. Leukemia 21, 1108–1109 (2007).

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