title: NUP98-HOXA9 bearing therapy-related myeloid neoplasm involves myeloid-committed cell and induces HOXA5, EVI1, FLT3, and MEIS1 expression.
abstract: BACKGROUND
  Chromosomal rearrangements involving NUP98 gene have been associated with human leukemias such as de novo AML, therapy-related AML (t-AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). Genetic fusion NUP98-HOXA9, caused by t(7;11)(p15;p15), is a recurrent cytogenetic alteration in de novo acute myeloid leukemia (AML) usually found in young Asian patients and its description in therapy-related myeloid neoplasms (t-MN) is rare. Only one Asian case with molecular demonstration of the NUP98-HOXA9 fusion has been reported in therapy-related leukemia. NUP98-HOXA9 leukemogenic mechanism is derived from the transcription factor activity of the chimeric protein, which enhances the expression of genes related to cellular differentiation arrest and proliferation.
  
  
  METHODS
  We studied a Caucasian woman with a therapy-related acute myeloid leukemia after Ewing's sarcoma. Molecular demonstration of the genetic fusion NUP98-HOXA9 was performed by RT-PCR, and gene expression was analyzed by real-time PCR, including four AML patients with MLL rearrangements for comparative analysis. Cytologic and flow cytometric analysis was also carried out.
  
  
  RESULTS
  After cytologic and flow cytometric analysis diagnostics was therapy-related myeloid neoplasm (t-MN). The major component of blasts in the acute leukemia was with neutrophilic differentiation, but 13% erythroid lineage blasts were also found. Cytogenetic and FISH analysis revealed t(7;11)(p15;p15) and NUP98-HOXA9 fusion gene was demonstrated. Gene expression analysis showed upregulation of EVI1 and MEIS1 in the index patient, both of them previously related to a worst outcome.
  
  
  CONCLUSIONS
  In this work, we include a detailed molecular, clinical, cytological, and cytometric study of the second t-AML bearing NUP98-HOXA9 genetic fusion.
authors.affiliation: Servicio de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-6895-7875
authors.initials: S
authors.lastname: Burillo-Sanz
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: R M
authors.initials: RM
authors.lastname: Morales-Camacho
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Caballero-Velázquez
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Vargas
authors.affiliation: Servicio de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: García-Lozano
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: J F
authors.initials: JF
authors.lastname: Falantes
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Prats-Martín
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Bernal
authors.affiliation: Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Pérez-Simón
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics*; D019468:Disease Management; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D022423:Myeloid Cells / Q000378:metabolism*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D016609:Neoplasms, Second Primary; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C400441:NUP98-HOXA9 fusion protein, human; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: NUP98; gene expression profiling; therapy-related AML