Original Article

Leukemia (2014) 28, 823–829; doi:10.1038/leu.2013.283; published online 18 October 2013

Cytogenetics and Molecular Genetics

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm

J Menezes1, F Acquadro1,2, M Wiseman2, G Gómez-López3, R N Salgado1, J G Talavera-Casañas4, I Buño5, J V Cervera6, S Montes-Moreno7, J M Hernández-Rivas8, R Ayala9, M J Calasanz10, M J Larrayoz10, L F Brichs11, M Gonzalez-Vicent12, D G Pisano3, M A Piris7, S Álvarez1 and J C Cigudosa1

  1. 1Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre—CNIO, Madrid, Spain
  2. 2NIMGenetics, R&D Department, Tres Cantos, Madrid, Spain
  3. 3Bioinformatic Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre—CNIO, Madrid, Spain
  4. 4Servicio de Hematología y Hemoterapia, Complejo Hospitalario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain
  5. 5Laboratorio de Genética Hematológica, Servicio de Hematología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
  6. 6Hematology Department, Hospital Universitario La Fe, Valencia, Spain
  7. 7Pathology Department, Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain
  8. 8IBSAL, IBMCC, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
  9. 9Hematology Department, Hospital Universitario 12 de octubre, Madrid, Spain
  10. 10Departamento de Genética, Universidad de Navarra, Pamplona, Spain
  11. 11Laboratori de Citologia Hematològica, Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), Barcelona, Spain
  12. 12Unidad de Trasplante Hematopoyético, Hospital Niño Jesus, Madrid, Spain

Correspondence: Dr JC Cigudosa, Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre—CNIO, Melchor Fernández Almagro, 3 28029, Madrid, Spain. E-mail: jccigudosa@cnio.es.

Received 27 June 2013; Revised 26 August 2013; Accepted 17 September 2013
Accepted article preview online 27 September 2013; Advance online publication 18 October 2013



Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37–99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12–16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.


BPDCN; blastic NK-cell lymphoma; TET2; ASXL1; IKAROS family