t(5;16)(q32;p13) NDE1/PDGFRB

2013-02-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology


Myelodysplastic syndromes


Two cases to date: a 27-year-old male patient with myelodysplasia with bone marrow and peripheral blood eosinophilia (Ross et al., 1987), and a 30-year-old female patient with Noonan Syndrome and a mutation in PTPN11 who developped a chronic myelomonocytic leukaemia (CMML) with dermal infiltration of eosinophils (La Starza et al., 2007). To be noted that Noonan Syndrome is a cancer-prone condition. In particular, Noonan syndrome patients are predisposed to juvenile myelomonocytic leukemia (JMML).


The 1987 patient was treated with prednisolone and lost-to follow up 5 months after diagnosis. The more recent patient was treated with imatinib and was remaining in complete remission 47 months after diagnosis (Cavazzini et al., 2009), confirming that PDGFRB translocations is associated with durable responses to imatinib in the majority of patients with Ph- chronic myeloproliferative/myelodysplastic disorders.


The involvement of NDE1 and PDGFRB in the translocation was ascertained in the recent case.

Genes Involved and Proteins

Gene name
PDGFRB (platelet-derived growth factor receptor, beta polypeptide)
Protein description
PDGFRB is made of five extracellular immunoglobulin loops, a transmembrane domain and a split intracellular kinase domain. PDGFA, PDGFB, PDGFC, and PDGFD form homo or heterodimers to bind PDGFRA and PDGFRB, inducing their dimerization and transduction of the signal to several signaling pathways (RAS/RAF/MAPK, PI3K/AKT/mTOR, PLCG and other pathways) involved in multiple cellular and developmental responses. PDGFRB signaling is particularly important in blood vessel formation and early hematopoiesis (review in Andrae et al., 2008). PDGFRB is a well known partner in different translocations found in chronic myeloproliferative disorders, myelodysplastic/myeloproliferative syndromes, and acute myeloid leukemias (Vizmanos 2005). There is high PDGFRB expression in metastatic medulloblastoma (Gilbertson and Clifford, 2003), chordoma (Tamborini et al., 2006), malignant peripheral nerve sheath tumor (Aoki et al., 2007), and in sarcomatoid non-small cell lung cancer (Tsao et al., 2011).
Gene name
NDE1 (nudE neurodevelopment protein 1)
Protein description
NDE1 is made of a N-terminal coiled-coil domain (self-association), dynein-binding domains, a domain interacting with PAFAH1B1, a region interacting with CENPF, a predicted disordered region that allows a bent back structure, and a C-terminal helix. This facilitates interaction of the C-terminal region with the N-terminal coiled-coil domain, homo or heterodimerization with NDEL1 and dynein interaction. NDE1, NDEL1 and PAFAH1B1 (LIS1) are DISC1 interactors. NDE1 plays a crucial role in microtubule organization and cell cycle progression, and is required for neuronal development. NDE1 localizes to the centrosome and mitotic spindle poles. Essential role in the cytoskeleton dynamics (mitosis, nuclei positioning, and cell migration) (review in Soares et al., 2012). NDE1 has been found to localise to the post-synaptic density. NDE1 plays an essential role in human cerebral cortex neurogenesis. Homozygous frameshift mutations in NDE1 was found in families with microlissencephaly, massive reduction in neuron numbers, and profound mental retardation; parents were unaffected (no heterozygote effects) (Bakircioglu et al., 2011; Alkuraya et al., 2011). Deletions and duplications at chromosomal 16p13.1, containing the NDE1 gene, are significantly over-represented in schizophrenia patients. Positive genetic association studies have been reported indicating that NDE1 and other DISC1 interactors may be implicated in schizophrenia (review in Bradshaw and Porteous, 2012). Of note, is that MYH11 and NDE1 are transcribed from overlapping opposing DNA strands, and, consequently, NDE1 is disrupted in 90% of cases with acute myeloid leukemia and inv(16)(p13q22) (Van der Reijden et al., 2010).

Result of the Chromosomal Anomaly


In-frame fusion of NDE1 exon 5 with PDGFRB exon 11 (the usual breakpoint in PDGFRB).N-terminal oligomerization domain of NDE1 (174 amino acids (aa)) fused to the transmembrane domain (TM) and the TYR kinase domain of PDGFRB (from aa 527, just before the TM domain, which starts at aa 533). The fusion protein should then contains 754 aa.


The oligomerization domain of NDE1 may mediate PDGFRB homodimerization and constitutive activation of its tyrosine kinase activity.


Pubmed IDLast YearTitleAuthors
215297512011Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].Alkuraya FS et al
184832172008Role of platelet-derived growth factors in physiology and medicine.Andrae J et al
175584202007Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB.Aoki M et al
215297522011The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis.Bakircioglu M et al
211957212012DISC1-binding proteins in neural development, signalling and schizophrenia.Bradshaw NJ et al
197376582009Trisomy 8 in PDGFRB-negative cells in a patient with imatinib-sensitive chronic myelomonocytic leukemia and t(5;16)(q33;p13), PDGFRB-NDE1 fusion.Cavazzini F et al
145933982003PDGFRB is overexpressed in metastatic medulloblastoma.Gilbertson RJ et al
173018212007A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome.La Starza R et al
36697761987A myelodysplastic syndrome with eosinophilia associated with a break in the short arm of chromosome 16.Ross FM et al
228436972012The mitosis and neurodevelopment proteins NDE1 and NDEL1 form dimers, tetramers, and polymers with a folded back structure in solution.Soares DC et al
171458092006Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.Tamborini E et al
217296462011Immunohistochemical overexpression of platelet-derived growth factor receptor-beta (PDGFR-β) is associated with PDGFRB gene copy number gain in sarcomatoid non-small-cell lung cancer.Tsao AS et al
200721482010The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB-MYH11-positive acute myeloid leukemia.Van der Reijden BA et al


Fusion gene

NDE1/PDGFRB NDE1 (16p13.11) PDGFRB (5q32) M|NDE1/PDGFRB NDE1 (16p13.11) PDGFRB (5q32) M t(5;16)(q32;p13)


Jean-Loup Huret

t(5;16)(q32;p13) NDE1/PDGFRB

Atlas Genet Cytogenet Oncol Haematol. 2013-02-01

Online version: http://atlasgeneticsoncology.org/haematological/1498/t(5;16)(q32;p13)