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Alterations of NFIA in Chronic Malignant Myeloid Diseases

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Alterations of NFIA in Chronic Malignant Myeloid Diseases Letters to the Editor 583 BACH2 is a B-cell specific transcription factor that induces 2Laboratoire d0He´matologie, CHU de Caen, Caen, France; 3 apoptosis in lymphoma cells and reduced expression has been De´parement de Genetique, Laboratoire Pasteur, Cerba, France and associated with poor prognostic outcome in diffuse large B-cell 4 lymphoma.7 Department of Haematology, John Radcliffe Hospital, Oxford, UK Our data also suggested that many components of the E-mail: [email protected] transforming growth factor-b (TGFb) signalling pathway are downregulated in PPBL (Supplementary Figure S3), including the tumour-suppressor molecule SMAD4 (Figure 1i; P ¼ 0.007). The TGFb pathway negatively regulates cell growth, and References inactivation of SMAD4 is present in over half of pancreatic 8 cancers and up to 35% of colorectal cancers. This is as far as 1 Mossafa H, Malaure H, Maynadie M, Valensi F, Schillinger F, we know the first description of the downregulation of SMAD4 Garand R et al. Persistent polyclonal B lymphocytosis with in a B-cell disorder. binucleated lymphocytes: a study of 25 cases. Groupe Francais PPBL represents a useful model for B-cell dysfunction as it d’Hematologie Cellulaire. Br J Haematol 1999; 104: 486–493. displays characteristics associated with benign (polyclonality, 2 Ozanne BW, Spence HJ, McGarry LC, Hennigan RF. Transcription factors control invasion: AP-1 the first among equals. Oncogene benign clinical course) and malignant disease (frequent chromo- 2007; 26: 1–10. somal abnormalities and aberrant B-cell morphology). Nearly all 3 Watanabe M, Sasaki M, Itoh K, Higashihara M, Umezawa K, Kadin studies to date have sought to characterize the morphological or ME et al. JunB induced by constitutive CD30-extracellular signal- genetic features of this disorder. This study represents not only regulated kinase 1/2 mitogen-activated protein kinase signaling the first detailed molecular investigation of PPBL, but also activates the CD30 promoter in anaplastic large cell lymphoma and includes a large proportion of all documented (o100) cases. reed-sternberg cells of Hodgkin lymphoma. Cancer Res 2005; 65: 7628–7634. Taken together these data suggest that PPBL although a benign 4 Willenbrock K, Kuppers R, Renne C, Brune V, Eckerle S, Weidmann disorder appears to share many molecular features of malig- E et al. Common features and differences in the transcriptome of nancy that can used to further our understanding of haemato- large cell anaplastic lymphoma and classical Hodgkin’s lymphoma. logical disease and clearly warrant further research. Haematologica 2006; 91: 596–604. 5 Roussel M, Roue G, Sola B, Mossafa H, Troussard X. Dysfunction of the Fas apoptotic signaling pathway in persistent polyclonal B-cell Acknowledgements lymphocytosis. Haematologica 2003; 88: 239–240. 6 Capra M, Nuciforo PG, Confalonieri S, Quarto M, Bianchi M, Nebuloni M et al. Frequent alterations in the expression of serine/ This work was funded by grants from the Leukaemia Research threonine kinases in human cancers. Cancer Res 2006; 66: Fund (CHL, HC, JB, JSW), the Julian Starmer-Smith Memorial Trust 8147–8154. (CHL) and Cancer Research UK (FP). 7 Sakane-Ishikawa E, Nakatsuka S, Tomita Y, Fujita S, Nakamichi I, 1 1 2 1 3 Takakuwa T et al. Prognostic significance of BACH2 expression in CH Lawrie , R Shilling , X Troussard , H Cattan , H Mossafa , diffuse large B-cell lymphoma: a study of the Osaka Lymphoma 1 1 1 4 F Pezzella , J Boultwood , JS Wainscoat and CSR Hatton Study Group. J Clin Oncol 2005; 23: 8012–8017. 1 Nuffield Department of Clinical Laboratory Sciences, 8 Miyaki M, Kuroki T. Role of Smad4 (DPC4) inactivation in human University of Oxford, John Radcliffe Hospital, Oxford, UK; cancer. Biochem Biophys Res Commun 2003; 306: 799–804. Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) Alterations of NFIA in chronic malignant myeloid diseases Leukemia (2009) 23, 583–585; doi:10.1038/leu.2008.228; To determine whether NFIA could have a function in early published online 28 August 2008 leukemogenesis, we searched for alterations of the NFIA gene in 89 chronic hematopoietic diseases by using array-comparative geno- mic hybridization (aCGH) and DNA sequencing. Our series The nuclear factor I (NFI) family of transcription factors comprised 35 chronic myelomonocytic leukemias and 54 myelo- comprises four members in humans, NFIA, NFIB, NFIC and proliferative disorders including 8 cases of polycythemia vera (PV), NFIX, which are involved in various cellular processes.1 The NFI 42 cases of essential thrombocythemia and 4 cases of idiopathic proteins comprise a DNA binding and dimerization domain in myelofibrosis. The aCGH experiments used high-density oligonu- their N-terminal half, which contains four cysteine residues cleotide microarrays (Hu-244A, Agilent Technologies, Massy, common to the four vertebrate members and conserved in the France) as previously described.10 aCGH was done on 84 samples. nonvertebrate orthologs, and a transactivation and repression We sequenced exons 2–11 of the gene for 48 samples (all chronic domain in their C-terminal half (Figure 1a). The NFIA gene, myelomonocytic leukemia, 5 essential thrombocythemia and 8 located in the 1p31 chromosomal region, has a function in PV), and only exon 2 for the remaining 41 myeloproliferative brain,2–4 ureteral and renal development3 as well as hemato- disorder samples (primers are available on demand). poiesis.5,6 Interactions of NFIA with CEBPa and PU.1 through We found alterations of the NFIA gene in two patients, microRNAs regulate granulocytic and monocytic differentiation, mentioned here as patients 1 and 2. respectively.5,6 NFIA regulates erythropoiesis through a network Patient 1, a 56-year-old woman, presented with erythrocytosis involving NR2C1, GATA1 and erythropoietin.7–9 and thrombocytosis in 2003. Bone marrow examination showed Leukemia Letters to the Editor 584 megakaryocyte proliferation with large and mature morphology Patient 2, a 60-year-old man without hematological ante- compatible with the diagnosis of essential thrombocythemia. cedent, was admitted to our Institute due to high white blood She received hydroxyurea from 2005 to 2006. At treatment cell count with monocytosis and splenomegaly. Bone marrow interruption, red cell mass increased, serum erythropoietin level examination led to the diagnosis of chronic myelomonocytic became low; a JAK2 V617F mutation was detected in 25% of leukemia type 1. Bone marrow karyotype showed a trisomy 19 alleles leading to the diagnosis of PV with thrombocytosis. in 17 of 20 mitoses. Sequencing of NFIA, using DNA extracted Resuming hydroxyurea therapy enabled stabilization of hemo- from peripheral white blood cells, detected a TGT-to-CGT globin level and platelet count. Routine examinations and mutation in exon 2. This mutation should lead to a cysteine-to- explorations never revealed signs of vascular events or hemato- arginine substitution at position 102 of the protein (Figure 1d). poietic evolution. Blood samples were collected when PV was aCGH and DNA microarrays data were not available for this diagnosed, 14 months away from all cytoreductive treatment. case. The patient was treated with hydroxyurea but developed Analysis of aCGH profile of DNA extracted from peripheral white acute myeloid leukemia (FAB type M5) 6 months later. blood cells detected a deletion in the 1p31.3 region including the To our knowledge, this is the first report of structural NFIA locus (Figures 1b and c). It was the only visible abnormality alterations of the NFIA gene in hematopoietic diseases. They of the profile. Sequencing of exons 2–11 of NFIA did not detect occurred in about 2% of our series of chronic myeloid diseases. any mutation. Gene expression profiling was performed on These alterations should lead to an inactivation of the protein. mRNA from this case and the other myeloproliferative disorder The point mutation targeted one of the conserved cysteine samples using Affymetrix U133 plus 2.0 DNA microarrays, as residues in the DNA-binding domain (Figure 1a), probably previously described,10 but did not detect differences in NFIA affecting the capacity of NFIA to bind DNA and/or to dimerize. mRNA levels when compared with normal blood samples. If confirmed by functional studies, it would position NFIA as a DNA binding Transactivation and dimerization and repression ccc c Exon1 2 3 11 Amino acid 102 -4 -3 -2 -1 0 +1 58.9Mb del(1)(p31.3) 60.8Mb 62.6Mb 64.4Mb Case 1 (PV) Case 2 (CMML) c.304T>C p.Cys102Arg Figure 1 Alteration of NFIA gene in chronic myeloid diseases. (a) Schematic representation of NFIA protein according to Gronostajski et al.1 The two main regions/domains of NFIA are shown in different colors. The amino-acid substitution in case 2, as derived from mutation shown in (d), targets the first conserved cysteine of the N-terminal domain. (b) aCGH profile of chromosome 1 in case 1 exhibits a deletion in the 1p31.3 region (arrow). The genomic profile established with CGH analytics software (Agilent Technologies), within the corresponding genomic interval (58.9–64.4 Mb) of the short arm of the chromosome 1 (hg17 human genome mapping; build 35 from NCBI, May 2004 version) shows a copy number loss that targets several genes including NFIA.(c) Detail of the 2.84 Mb deleted region, which is flanked by telomeric and centromeric breaks within chr1:60 089.982–60 103.734 (within the HOOK1 gene) and chr1:62 944.961–62,962.416 (50 of DOCK7) intervals, respectively. (d) Sequence of the mutated NFIA allele in case 2, demonstrating base change in the reverse sequence at the position indicated by the arrow. Leukemia Letters to the Editor 585 new tumor suppressor gene and provide explanations for References previous results.11 The NFIC gene is already considered as a potential tumor suppressor gene.12 The fact that the NFIA- 1 Gronostajski RM.
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