Bartlomiej Przychodzen

Publications (7)65.48 Total impact

• Article: STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia.

  Andres Jerez, Michael J Clemente, Hideki Makishima, Hanna Koskela, Francis Leblanc, Kwok Peng Ng, Thomas Olson, Bartlomiej Przychodzen, Manuel Afable, Ines Gomez-Segui, [......], Eric D Hsi, Kathy McGraw, Dan Zhang, Marcin W Wlodarski, Kimmo Porkka, Mikkael A Sekeres, Alan List, Satu Mustjoki, Thomas P Loughran, Jaroslaw P Maciejewski
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  ABSTRACT: Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions.
  Blood 08/2012; 120(15):3048-57. · 9.90 Impact Factor
• Article: Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia.

  Sarah Abu Kar, Anna M Jankowska, Hideki Makishima, Valeria Visconte, Andres Jerez, Yuka Sugimoto, Hideki Muramatsu, Fabiola Traina, Manuel Afable, Kathryn Guinta, Ramon V Tiu, Bartlomiej Przychodzen, Hirotoshi Sakaguchi, Seiji Kojima, Mikkael A Sekeres, Alan F List, Michael A McDevitt, Jaroslaw P Maciejewski
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  ABSTRACT: Background Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations can be detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and the closely related diseases.Methods We genotyped a cohort of patients with chronic myelomoncytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and of the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints.ResultsMutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (p=.047) and DNMT3A (p=.015). RAS mutations had impact on overall surviva; in sAML (p=.0456). By comparison, our screen for juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or 3 spliceosomal genes.ConclusionsSRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinct from a profile seen in juvenile myelomonocytic leukemia. Our data also suggests that spliceosomal mutations are of ancestral origin.
  Haematologica 07/2012; · 6.42 Impact Factor
• Article: Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis.

  Andres Jerez, Yuka Sugimoto, Hideki Makishima, Amit Verma, Anna M Jankowska, Bartlomiej Przychodzen, Valeria Visconte, Ramon V Tiu, Christine L O'Keefe, Azim M Mohamedali, [......], Kathy McGraw, Hideki Muramatsu, Alison R Moliterno, Mikkael A Sekeres, Michael A McDevitt, Seiji Kojima, Alan List, Jacqueline Boultwood, Ghulam J Mufti, Jaroslaw P Maciejewski
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  ABSTRACT: Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features.
  Blood 05/2012; 119(25):6109-17. · 9.90 Impact Factor
• Article: Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited.

  Andres Jerez, Lukasz P Gondek, Anna M Jankowska, Hideki Makishima, Bartlomiej Przychodzen, Ramon V Tiu, Christine L O'Keefe, Azim M Mohamedali, Denise Batista, Mikkael A Sekeres, Michael A McDevitt, Ghulam J Mufti, Jaroslaw P Maciejewski
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  ABSTRACT: Interstitial deletions of chromosome 5q are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), pointing toward the pathogenic role of this region in disease phenotype and clonal evolution. The higher level of resolution of single-nucleotide polymorphism array (SNP-A) karyotyping may be used to find cryptic abnormalities and to precisely define the topographic features of the genomic lesions, allowing for more accurate clinical correlations. We analyzed high-density SNP-A karyotyping at diagnosis for a cohort of 1,155 clinically well-annotated patients with malignant myeloid disorders. results: We identified chromosome 5q deletions in 142 (12%) of 1,155 patients and uniparental disomy segments (UPD) in four (0.35%) of 1,155 patients. Patients with deletions involving the centromeric and telomeric extremes of 5q have a more aggressive disease phenotype and additional chromosomal lesions. Lesions not involving the centromeric or telomeric extremes of 5q are not exclusive to 5q- syndrome but can be associated with other less aggressive forms of MDS. In addition, larger 5q deletions are associated with either del(17p) or UPD17p. In 31 of 33 patients with del(5q) AML, either a deletion involving the centromeric and/or telomeric regions or heterozygous mutations in NPM1 or MAML1 located in 5q35 were present. Our results suggest that the extent of the affected region on 5q determines clinical characteristics that can be further modified by heterozygous mutations present in the telomeric extreme.
  Journal of Clinical Oncology 02/2012; 30(12):1343-9. · 18.37 Impact Factor
• Article: CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia.

  Hideki Makishima, Anna M Jankowska, Michael A McDevitt, Christine O'Keefe, Simon Dujardin, Heather Cazzolli, Bartlomiej Przychodzen, Courtney Prince, John Nicoll, Harish Siddaiah, Mohammed Shaik, Hadrian Szpurka, Eric Hsi, Anjali Advani, Ronald Paquette, Jaroslaw P Maciejewski
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  ABSTRACT: Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL). Microdeletions on chromosomes 17q11.2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML.
  Blood 02/2011; 117(21):e198-206. · 9.90 Impact Factor
• Article: Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value.

  Alexander E Smith, Azim M Mohamedali, Austin Kulasekararaj, ZiYi Lim, Joop Gäken, Nicholas C Lea, Bartlomiej Przychodzen, Syed A Mian, Erick E Nasser, Claire Shooter, Nigel B Westwood, Corinna Strupp, Norbert Gattermann, Jaroslaw P Maciejewski, Ulrich Germing, Ghulam J Mufti
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  ABSTRACT: Mutations in the TET2 gene are frequent in myeloid disease, although their biologic and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using "next-generation" sequencing for TET2 aberrations, 91 of whom were also subjected to single-nucleotide polymorphism 6.0 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥ 10%, were identified in 39 of 320 (12%) myelodysplastic syndrome and 16 of 35 (46%) chronic myelomonocytic leukemia patients (P < .001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. "Deeper" sequencing of 96 patient samples identified 4 additional mutations (RMA, 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells, in addition to CD34(+) and total bone marrow cells (23.5%, 38.5%, and 43% RMA, respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression, or the JAK2V617F 46/1 haplotype between TET2-mutated and nonmutated patients. There was no significant prognostic association between TET2 mutations and World Health Organization subtypes, International Prognostic Scoring System score, cytogenetic status, or transformation to acute myeloid leukemia. On multivariate analysis, age (> 50 years) was associated with a higher incidence of TET2 mutation (P = .02).
  Blood 11/2010; 116(19):3923-32. · 9.90 Impact Factor
• Article: Silicosection and elucidation of the plant circadian clock using Bayesian classifiers and new genemining algorithm.

  Sandra Smieszek, Rainer Richter, Bartlomiej Przychodzen, Jaroslaw Maciejewski
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  ABSTRACT: Datasets with a high dimensional feature space, advancing statistical methods, and computational efficiency were analyzed to uncover the rules of the circadian rhythms. The aim of the study was to uncover the identity, the dynamic behavior, and the interactions among the components of the circadian clock. Transcriptional profiling has exposed the regulon conferring benefits for circadian biology and bioinformatics. Circadian plant time course gene expression data was examined, this was the prerequisite for Naive Bayes classifiers which were trained and led to expression model with a success rate of up to 87%. The model showed new combinatorial rules, including presence of elements and their frequencies in driving particular phases. Implementation of Genemining V2.3 multipotent algorithm showed the specific combinations of elements responsible for expression patterns, highlighting the role of GATA motifs. State-of-the-art technologies allowed for a model in silico, the first such model was made using time course circadian data.
  Advances in experimental medicine and biology 01/2010; 680:43-56. · 1.09 Impact Factor