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in Oncology and Haematology

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Leukaemia Section Short Communication t(5;16)(q32;p13) NDE1/PDGFRB Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: February 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0516q32p13ID1498.html DOI: 10.4267/2042/51145 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Cytogenetics Disease Cytogenetics morphological Myelodysplastic syndromes The t(5;16)(q32;p13) was the sole abnormality in both Clinics cases. A transient trisomy 8 was found in t(5;16)-negative Two cases to date: a 27-year-old male patient with cells during course of the disease in the case reported in myelodysplasia with bone marrow and peripheral blood La Starza et al., 2007, and Cavazzini et al., 2009. eosinophilia (Ross et al., 1987), and a 30-year-old female patient with Noonan Syndrome and a involved and in PTPN11 who developped a chronic myelomonocytic leukaemia (CMML) with dermal infiltration of PDGFRB eosinophils (La Starza et al., 2007). To be noted that Location Noonan Syndrome is a cancer-prone condition. In At the edge of 5q32-5q33 particular, Noonan syndrome patients are predisposed to juvenile myelomonocytic leukemia (JMML). PDGFRB is made of five extracellular immunoglobulin Treatment loops, a transmembrane domain and a split intracellular The 1987 patient was treated with prednisolone and kinase domain. PDGFA, PDGFB, PDGFC, and lost-to follow up 5 months after diagnosis. PDGFD form homo or heterodimers to bind PDGFRA The more recent patient was treated with imatinib and and PDGFRB, inducing their dimerization and was remaining in complete remission 47 months after transduction of the signal to several signaling pathways diagnosis (Cavazzini et al., 2009), confirming that (RAS/RAF/MAPK, PI3K/AKT/mTOR, PLCG and PDGFRB translocations is associated with durable other pathways) involved in multiple cellular and responses to imatinib in the majority of patients with developmental responses. Ph- chronic myeloproliferative/myelodysplastic PDGFRB signaling is particularly important in blood disorders. vessel formation and early hematopoiesis (review in Andrae et al., 2008). Genetics PDGFRB is a well known partner in different translocations found in chronic myeloproliferative Note disorders,myelodysplastic/myeloproliferative The involvement of NDE1 and PDGFRB in the syndromes, and acute myeloid leukemias (Vizmanos translocation was ascertained in the recent case. 2005).

Atlas Genet Cytogenet Oncol Haematol. 2013; 17(8) 565 t(5;16)(q32;p13) NDE1/PDGFRB Huret JL

There is high PDGFRB expression in metastatic (TM) and the TYR kinase domain of PDGFRB (from medulloblastoma (Gilbertson and Clifford, 2003), aa 527, just before the TM domain, which starts at aa chordoma (Tamborini et al., 2006), malignant 533). The fusion protein should then contains 754 aa. peripheral nerve sheath tumor (Aoki et al., 2007), and Oncogenesis in sarcomatoid non-small cell lung cancer (Tsao et al., The oligomerization domain of NDE1 may mediate 2011). PDGFRB homodimerization and constitutive activation NDE1 of its tyrosine kinase activity. Location 16p13.11 References Protein Ross FM, Hamilton M, Cook MK, Irving JB. A myelodysplastic syndrome with eosinophilia associated with a break in the short NDE1 is made of a N-terminal coiled-coil domain arm of 16. Leukemia. 1987 Sep;1(9):680-1 (self-association), dynein-binding domains, a domain interacting with PAFAH1B1, a region interacting with Gilbertson RJ, Clifford SC. PDGFRB is overexpressed in metastatic medulloblastoma. Nat Genet. 2003 Nov;35(3):197-8 CENPF, a predicted disordered region that allows a bent back structure, and a C-terminal helix. Vizmanos JL.. PDGFRB (platelet-derived growth factor receptor, beta polypeptide). Atlas Genet Cytogenet Oncol This facilitates interaction of the C-terminal region Haematol. July 2005. with the N-terminal coiled-coil domain, homo or heterodimerization with NDEL1 and dynein Tamborini E, Miselli F, Negri T, Lagonigro MS, Staurengo S, Dagrada GP, Stacchiotti S, Pastore E, Gronchi A, Perrone F, interaction. NDE1, NDEL1 and PAFAH1B1 (LIS1) are Carbone A, Pierotti MA, Casali PG, Pilotti S.. Molecular and DISC1 interactors. NDE1 plays a crucial role in biochemical analyses of platelet-derived growth factor receptor microtubule organization and progression, (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin and is required for neuronal development. NDE1 Cancer Res. 2006 Dec 1;12(23):6920-8. localizes to the and mitotic spindle poles. Aoki M, Nabeshima K, Koga K, Hamasaki M, Suzumiya J, Essential role in the cytoskeleton dynamics (mitosis, Tamura K, Iwasaki H.. Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by nuclei positioning, and cell migration) (review in platelet-derived growth factor-BB. Lab Invest. 2007 Soares et al., 2012). NDE1 has been found to localise Aug;87(8):767-79. Epub 2007 Jun 11. to the post-synaptic density. NDE1 plays an essential La Starza R, Rosati R, Roti G, Gorello P, Bardi A, Crescenzi B, role in human cerebral cortex neurogenesis. Pierini V, Calabrese O, Baens M, Folens C, Cools J, Marynen Homozygous frameshift in NDE1 was found P, Martelli MF, Mecucci C, Cuneo A.. A new NDE1/PDGFRB in families with microlissencephaly, massive reduction fusion transcript underlying chronic myelomonocytic leukaemia in neuron numbers, and profound mental retardation; in Noonan Syndrome. Leukemia. 2007 Apr;21(4):830-3. Epub 2007 Feb 15. parents were unaffected (no heterozygote effects) (Bakircioglu et al., 2011; Alkuraya et al., 2011). Andrae J, Gallini R, Betsholtz C.. Role of platelet-derived Deletions and duplications at chromosomal 16p13.1, growth factors in physiology and medicine. Genes Dev. 2008 May 15;22(10):1276-312. doi: 10.1101/gad.1653708. containing the NDE1 , are significantly over- (REVIEW) represented in schizophrenia patients. Positive genetic Cavazzini F, Bardi A, Ciccone M, Rigolin GM, Gorello P, La association studies have been reported indicating that Starza R, Mecucci C, Cuneo A.. Trisomy 8 in PDGFRB- NDE1 and other DISC1 interactors may be implicated negative cells in a patient with imatinib-sensitive chronic in schizophrenia (review in Bradshaw and Porteous, myelomonocytic leukemia and t(5;16)(q33;p13), PDGFRB- 2012). Of note, is that MYH11 and NDE1 are NDE1 fusion. Cancer Genet Cytogenet. 2009 Oct;194(1):67-9. transcribed from overlapping opposing DNA strands, doi: 10.1016/j.cancergencyto.2009.04.026. and, consequently, NDE1 is disrupted in 90% of cases Van der Reijden BA, Massop M, Simons A, de Witte T, with acute myeloid leukemia and inv(16)(p13q22) (Van Breuning M, Jansen JH.. The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB-MYH11-positive acute der Reijden et al., 2010). myeloid leukemia. Leukemia. 2010 Apr;24(4):857-9. doi: 10.1038/leu.2009.290. Epub 2010 Jan 14. Result of the chromosomal Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS, Felie JM, Hill RS, Barry BJ, Partlow JN, Gascon GG, Kentab A, anomaly Jan M, Shaheen R, Feng Y, Walsh CA.. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am J Hybrid gene Hum Genet. 2011 May 13;88(5):536-47. doi: Description 10.1016/j.ajhg.2011.04.003. Epub 2011 Apr 28. In-frame fusion of NDE1 exon 5 with PDGFRB exon Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B, 11 (the usual breakpoint in PDGFRB). Barak T, Yilmaz S, Caglayan O, Dincer A, Nicholas AK, Quarrell O, Springell K, Karbani G, Malik S, Gannon C, Fusion protein Sheridan E, Crosier M, Lisgo SN, Lindsay S, Bilguvar K, Gergely F, Gunel M, Woods CG.. The essential role of Description centrosomal NDE1 in human cerebral cortex neurogenesis. N-terminal oligomerization domain of NDE1 (174 Am J Hum Genet. 2011 May 13;88(5):523-35. doi: amino acids (aa)) fused to the transmembrane domain 10.1016/j.ajhg.2011.03.019. Epub 2011 Apr 28.

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Tsao AS, Wei W, Kuhn E, Spencer L, Solis LM, Suraokar M, Soares DC, Bradshaw NJ, Zou J, Kennaway CK, Hamilton RS, Lee JJ, Hong WK, Wistuba II.. Immunohistochemical Chen ZA, Wear MA, Blackburn EA, Bramham J, Bottcher B, overexpression of platelet-derived growth factor receptor-beta Millar JK, Barlow PN, Walkinshaw MD, Rappsilber J, Porteous (PDGFR-b) is associated with PDGFRB gene copy number DJ.. The mitosis and neurodevelopment proteins NDE1 and gain in sarcomatoid non-small-cell lung cancer. Clin Lung NDEL1 form dimers, tetramers, and polymers with a folded Cancer. 2011 Nov;12(6):369-74. doi: back structure in solution. J Biol Chem. 2012 Sep 10.1016/j.cllc.2011.02.002. Epub 2011 May 17. 21;287(39):32381-93. Epub 2012 Jul 27.

Bradshaw NJ, Porteous DJ.. DISC1-binding proteins in neural This article should be referenced as such: development, signalling and schizophrenia. Neuropharmacology. 2012 Mar;62(3):1230-41. doi: Huret JL. t(5;16)(q32;p13) NDE1/PDGFRB. Atlas Genet 10.1016/j.neuropharm.2010.12.027. Epub 2010 Dec 31. Cytogenet Oncol Haematol. 2013; 17(8):565-567. (REVIEW)

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