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Mutation Analysis of Son of Sevenless in Juvenile Myelomonocytic Leukemia

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Mutation Analysis of Son of Sevenless in Juvenile Myelomonocytic Leukemia Letters to the Editor 1108 3 Licht JD. Reconstructing a disease: what essential features of the the development of acute promyelocytic leukemia in transgenic retinoic acid receptor fusion oncoproteins generate acute promye- mice. Proc Natl Acad Sci USA 2000; 97: 13306–13311. locytic leukemia? Cancer Cell 2006; 9: 73–74. 10 Sternsdorf T, Phan VT, Maunakea ML, Ocampo CB, Sohal J, 4 Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. Silletto A et al. Forced retinoic acid receptor alpha homodimers A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 prime mice for APL-like leukemia. Cancer Cell 2006; 9: 81–94. genes as a therapeutic target of imatinib in idiopathic hypereosino- 11 Kwok C, Zeisig BB, Dong S, So CW. Forced homo-oligomerization philic syndrome. N Engl J Med 2003; 348: 1201–1214. of RARalpha leads to transformation of primary hematopoietic 5 Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human cells. Cancer Cell 2006; 9: 95–108. Fip1 is a subunit of CPSF that binds to U-rich RNA elements and 12 Palaniswamy V, Moraes KC, Wilusz CJ, Wilusz J. Nucleophosmin stimulates poly(A) polymerase. EMBO J 2004; 23: 616–626. is selectively deposited on mRNA during polyadenylation. Nat 6 Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Struct Mol Biol 2006; 13: 429–435. Arnoulet C et al. A new morphologic classification system for acute 13 Rego EM, Ruggero D, Tribioli C, Cattoretti G, Kogan S, Redner RL promyelocytic leukemia distinguishes cases with underlying PLZF/ et al. Leukemia with distinct phenotypes in transgenic mice RARA gene rearrangements. Group Francais de Cytogenetique expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Hematologique, UK Cancer Cytogenetics Group and BIOMED 1 Oncogene 2006; 25: 1974–1979. European Community-Concerted Action Molecular Cytogenetic Diag- 14 Kamashev D, Vitoux D, De The H. PML-RARA-RXR oligomers nosis in Haematological Malignancies. Blood 2000; 96: 1287–1296. mediate retinoid and rexinoid/cAMP cross-talk in acute 7 Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, promyelocytic leukemia cell differentiation. J Exp Med 2004; Kerndrup G et al. A pediatric approach to the WHO classification of 199: 1163–1174. myelodysplastic and myeloproliferative diseases. Leukemia 2003; 15 Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P et al. 17: 277–282. Activation of FIP1L1-PDGFRalpha requires disruption of the 8 Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ. Altered myeloid juxtamembrane domain of PDGFRalpha and is FIP1L1-indepen- development and acute leukemia in transgenic mice expressing dent. Proc Natl Acad Sci USA 2006; 103: 8078–8083. PML-RAR alpha under control of cathepsin G regulatory sequences. 16 Wodzinski MA, Watmore AE, Lilleyman JS, Potter AM. Blood 1997; 89: 376–387. Chromosomes in childhood acute lymphoblastic leukaemia: 9 Zimonjic DB, Pollock JL, Westervelt P, Popescu NC, Ley TJ. karyotypic patterns in disease subtypes. J Clin Pathol 1991; 44: Acquired, nonrandom chromosomal abnormalities associated with 48–51. Mutation analysis of Son of Sevenless in juvenile myelomonocytic leukemia Leukemia (2007) 21, 1108–1109. doi:10.1038/sj.leu.2404620; cardiac defects. PTPN11 encodes SHP-2, a non-receptor published online 22 February 2007 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 Ras proteins are molecular switches that cycle between inactive part, through the Ras pathway.6 Infants with NS are predisposed GDP-bound and active GTP-bound states.1 Growth factors to MPD resembling JMML (NS/JMML).7 Interestingly, specific activate Ras by recruiting the nucleotide exchange factor Son of germline PTPN11 mutations were identified in most cases of NS/ Sevenless (SOS1) to the plasma membrane.2,3 Ras signaling has JMML and somatic mutations, largely restricted to patients profound consequences for the cell and unregulated Ras without clinical NF1 or mutations in RAS, occur in B35% of activation is a hallmark of cancer. Germline mutations of genes JMML cases.7 activating this pathway can also cause developmental disorders, KRAS germline mutations are a rare cause of NS.1,8 These such as Noonan (PTPN11, KRAS), Costello (HRAS), and cardio- mutations encode specific gain-of-function alleles that have facio-cutaneous syndromes (KRAS, BRAF, MEK1/2), as well as been in part studied in detail and shown to exhibit effects that neurofibromatosis type 1 (NF1).1 are less pronounced than those exhibited by cancer associated Juvenile myelomonocytic leukemia (JMML) is a myeloproli- mutant K-RasG12D, thus offering an explanation why these ferative disorder (MPD) characterized by leukocytosis, tissue germline mutations are tolerated during embryonic develop- infiltration by malignant cells, and in vitro hypersensitivity of ment.8 Taken together, there is a close connection between myeloid progenitors to granulocyte–macrophage colony stimu- JMML and NS, both being model diseases for somatic and lating factor.4,5 The incidence of JMML is increased in children germline events leading to increased signaling through the Ras with neurofibromatosis type 1 (NF1).5 NF1, which is diagnosed pathway, respectively (Figure 1). Nevertheless, in B25% of in B11% of all JMML cases, is an autosomal dominant cancer JMML cases and B50% of NS cases, no mutations are identified, predisposition syndrome caused by mutations of NF1 coding for suggesting that mutations in other genes of this pathway may be neurofibromin, a GTPase activating protein (GAP) for Ras.5 involved in human disease. JMML cells from patients with NF1 show biallelic NF1 After the recent discovery of SOS1 germline mutations in 10% inactivation and elevated Ras . GTP levels.5 Approximately of cases of NS (MZ, paper in preparation),2,3 we screened JMML 25% of JMML cases have somatic RAS mutations, which are specimens from patients without NF1 that lacked mutations in identified in patients who do not have NF1.5 These data and PTPN11 or RAS for SOS1 mutations. Diagnostic blood or bone studies in mouse models underscore a crucial role of hyper- marrow cells from patients with NS/JMML (n ¼ 5) or JMML active Ras in the pathogenesis of JMML.5 (n ¼ 44) enrolled in the EWOG-MDS study or from patients Germline PTPN11 mutations cause 50% of cases of Noonan diagnosed in the US were collected and analyzed with informed syndrome (NS; MIM 163950),5 an autosomal dominant disorder consent and Institutional Review Board-approved protocols. The characterized by short stature, distinct facial features, and entire coding sequence of SOS1 was sequenced in 22 samples. Leukemia Letters to the Editor 1109 1 Growth factor Department of Pediatrics, University of Freiburg, Freiburg, Germany; 2Department of Structural Biology, Max Planck Institute of active Molecular Physiology, Dortmund, Germany; 3Institute of Human Genetics, University of Erlangen-Nurem- Ras Ras Grb2 berg, Erlangen, Germany; 4Division of Pediatric Hematology and Oncology, University Shc SOS1 NF1 Gab2 Children’s Hospital Zurich, Zurich, Switzerland; Raf 5Department of Pediatrics and the Comprehensive Cancer SHP-2 Center, University of California at San Francisco, San Francisco, CA, USA; RTK 6 MEK Children’s Cancer Research Institute, St Anna Children’s Hospital, Vienna, Austria; 7Department of Pediatrics, Skejby Hospital, Aarhus University, Nucleus Aarhus, Denmark; 8Dutch Childhood Oncology Group, the Hague, Erasmus Figure 1 Simplified Ras-signaling pathway. Proteins involved in the pathogenesis of Noonan syndrome (germline mutations of Medical Center-Sophia Children’s Hospital, Rotterdam, PTPN11 (SHP-2), KRAS or SOS1) or JMML (biallelic inactivation The Netherlands; 9 of NF1 or somatic mutations of PTPN11, KRAS or NRAS) are indicated Harvard Partners Center for Genetics and Genomics and in black. Harvard Medical School, Boston, MA, USA; 10Department of Pediatrics, University of Tu¨bingen, Tu¨bingen, Germany; 11Division of Genetics, Department of Medicine, Children’s The remaining 27 JMML specimens were screened for mutations Hospital Boston and Harvard Medical School, Boston, MA, in mutational hotspots of NS including exons 3, 6, 7, 8, 10, 11, USA; 12 12, 13, 14, 16 and 19 (MZ, manuscript in preparation).2,3 No Department of Pediatric Hematology/Oncology, Charles pathologic mutations were detected. However, we identified a University, University Hospital Motol, Prague, Czech Republic; 13 known polymorphism, c.1964 C-T (P655L), in three JMML Cancer Biology Program, Division of Hematology/Oncology, specimens. Department of Medicine, Beth Israel Deaconess Medical Center We conclude that SOS1 does not act as a proto-oncogene in and Harvard Medical School, Boston, MA, USA; 14 JMML, which is in contrast to the previous two NS genes, Department of Pediatrics, St Anna Children’s Hospital, PTPN11 and KRAS. Further candidate gene approaches will be Vienna, Austria; 15 necessary to identify JMML genes mutated in 25% of cases Oncoematologia Pediatrica, Fondazione IRCCS Policlinico without a clinical diagnosis of NF1 or mutations in PTPN11 or San Matteo, University of Pavia, Pavia, Italy RAS. Besides SOS1, we have recently screened most exons of E-mail: [email protected] SHC1, GRB2, and GAB1 and not identified any mutations in 15 patients with JMML and two patients with NS/JMML. Addition- References ally, no mutations have been identified in MEK1 (exons 2 and 3) or MEK2 (exon 2) in seven patients with isolated JMML and two 1 Downward J. Signal transduction. Prelude to an anniversary for the patients with NS/JMML. RAS oncogene. Science 2006; 314: 433–434. 2 Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007; 39: 70–74. Acknowledgements 3 Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 2007; 39: 75–79.
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