Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10

Oakley, Karen L.; Han, Yufen; Vishwakarma, Bandana Ajay; Chu, Su; Bhatia, Ravi; Gudmundsson, Kristbjorn O.; Keller, Jonathan R.; Chen, Xiongfong; Vasko, Vasyl; Jenkins, Nancy A.; Copeland, Neal G.; Du, Yang

doi:10.1182/blood-2011-10-388710

Cited by 80 publications

(98 citation statements)

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“…45 We find upregulation of HEMGN, (a transcription factor implicated in myeloid self-renewal 36 ), FHL2 (enhanced expression of which leads to enhanced cell cycle entry), FZD6 (shown to be involved in the pathologically reactivation of the Wnt/Fzd-mediated self-renewal signals that are enlisted during B-cell development and may be pathologically reactivated in the neoplastic transformation of mature B cells), and SETBP1 (overexpression of which promotes the self-renewal of myeloid progenitors [46][47][48] ). It is interesting that similar cellular processes are affected in the IKZF1 deleted cases, while none of the genes deregulated in IKZF1 deleted adult BCP-ALL are found deregulated in this pediatric IKZF1 deleted AML cohort.…”

Section: A B C D E Fmentioning

confidence: 99%

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nby controlling transcriptional regulators, such as GATA1 and RUNX1. 18,20 Although IKZF1 is not required for the initial differentiation towards granulocytes and monocytes, IKZF1 represses differentiation of the basophilic granulocyte lineage and promotes early maturation and survival of the neutrophil granulocyte lineage. 17,21,22 In pediatric AML, monosomy 7 is found in only 4%-5% of patients. The 5-year OS and EFS of pediatric AML patients with monosomy 7 with or without additional cytogenetic or chromosomal aberrations are poor. 23 In adult AML, monosomy 7 is the most frequent single monosomy and has a similar poor 4-year OS as compared to other single autosomal monosomies. 24 Deletions of the short arm of chromosome 7, 7p (del7p) were recurrently found in adult de novo AML and secondary AML developed from myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). [25][26][27] Furthermore, 7p deletions were mapped to the IKZF1 locus and it was shown that loss of IKZF1 is acquired during the progression of MPN to secondairy AML, indicating that loss of IKZF1 contributes to the transformation from MPN to AML. 25 Together, these studies demonstrate that IKZF1 may play a role in myeloid differentiation and that loss of IKZF1 may contribute to myeloid oncogenesis. We, therefore, hypothesized that, in pediatric AML patients with monosomy 7, IKZF1 may be an important player. In this study, we analyzed the frequency of IKZF1 deletions in a pediatric AML cohort, and studied the difference in gene expression of cases with focal IKZF1 deletions, and cases with monosomy 7. Methods Patients' samplesSamples were provided by the Dutch Childhood Oncology Group (DCOG, the Netherlands), the AML-Berliner-FrankfurtMünster Study Group (Germany and Czech Republic), the SaintLouis Hospital (France), and the Royal Hospital for Sick Children (UK). Isolation of genomic DNA and total cellular RNA was performed using Trizol reagent. Each study group provided morphological and cytogenetic classification and clinical data. Institutional review board approval for these studies had been obtained in the participating centers. Detection of deletions and mutations of IKZF1Multiplex ligation-dependent probe amplification (MLPA) was performed using the p335-B1;ALL-IKZF1 kit (MRC Holland, Amsterdam, the Netherlands; data available at http: //www.mlpa.com). The data were analyzed with GeneMarker v. 1.85 (SoftGenetics, State College, Pennsylvania, USA). Data were normalized to reference probes and control samples. A deletion was defined as a peak ratio below 0.75; an amplification was defined as a peak ratio above 1.25.Array comparative genomic hybridization (Array-CGH) was performed using the human genome CGH Microarray 105K (Agilent Technologies, Santa Clara, California, USA) according to the manufacturer's protocol; data were analyzed with Genomic Workbench v. 5.0.14 (Agilent Technologies, Santa Clara, California, USA).Direct sequencing was used to analyze mutations or frameshif...

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Section: A B C D E Fmentioning

confidence: 99%

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

et al. 2015

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“…68 Evidence suggests that SETBP1 is a protooncogene with overexpression in myeloid progenitors leading to enhanced self renewal. 69 SETBP1 binds SET nuclear oncoprotein and inhibits protein phosphatase type 2a, a tumor suppressor.…”

Section: 55mentioning

confidence: 99%

“…69 Its strict role in leukemogenesis remains unclear. Importantly, however, several studies have shown SETBP1 to be a poor prognostic marker in myeloid diseases.…”

Section: 55mentioning

confidence: 99%

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Chang

Dvorak

Loh

2014

Blood

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Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.

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“…25 LSK cells were infected with pLKO.1 lentivirus containing shRNAs targeting Brcc3 (Targeting sequences: shRNA, 5'-CCCACCCT-CATATAACTGTTT-3') or negative control shRNA (Sigma, SHC002). Lentiviral infections were performed twice by spinoculation.…”

Section: Shrna Knockdown and Colony Formation Assay Of Lsk Cellsmentioning

confidence: 99%

BRCC3 mutations in myeloid neoplasms

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nUIMC1, FAM175A, BABAM1, BRE, BARD1, BRCC3 and BRCA1 and participates in DNA double-strand break (DSB) repair. 17 DSBs are associated with genomic instability, cell death 18 and carcinogenesis. 19 To repair DSBs, cells use both homologous recombination (HR), which uses sister-chromatid alleles as templates in late S and G 2 , and non-homologous end joining (NHEJ) which can operate in all phases of the cell cycle but often leaves small deletions, possibly gene inactivating at the site of repair. 20 The BRISC complex comprises the following proteins: FAM175B/ABRO1, BRCC3/BRCC36, BRE/BRCC45 and MERIT40/NBA1.Here, we report that somatic defects of BRCC3 are acquired in various myeloid neoplasms and have consequences at the cellular, and perhaps the clinical level. Methods PatientsBone marrow aspirates or blood were collected from the patients with various myeloid neoplasms seen at the Cleveland Clinic, University of Tokyo and Münchner Leukämielabor GmbH (MLL) (Online Supplementary Table S1). Informed consent for sample collection was obtained according to protocols approved by the institutional review boards in accordance with the Declaration of Helsinki. Diagnoses were confirmed according to 2008 World Health Organization classification criteria. 21 A total of 1778 patients were enrolled in this study (Online Supplementary Table S1). Next generation sequencingWhole exome sequencing (WES) was performed as previously reported. 4,6 Briefly, tumor DNAs were extracted from patients' bone marrow cells. For germ-line controls, DNA was obtained from paired CD3 + T cells. For targeted detection of sequence alterations, confirmation of WES and assessment of variant allelic frequency (VAF), we applied deep sequencing to targeted exons, as previously described. 6,22 Briefly, each targeted exon was amplified with each pair of primers, generating 200bp fragments on average. These amplicons were subjected to massive parallel sequencing (Illumina, San Diego, CA, USA) using TruSeq custom primers (Illumina) and SureSelect (Agilent, Santa Clara, CA, USA) with paired-end reads, according to the manufacture's instruction. Some of these procedures were followed by confirmation using Sanger sequencing, as previously described. 13 Annotations by NCBI reference numbers of the genes affected by somatic mutations are summarized in Online Supplementary Table S2. Cytogenetics and single nucleotide polymorphism-array analysesTechnical details about sample processing and data analyses for single nucleotide polymorphism-array (SNP-A) have been previously described.23 Affymetrix 250K and 6.0 Kit (Affymetrix) were used. Germ-line copy number variants in our internal database or in a publicly available database (Database of Genomic Variants) (http://dgv.tcag.ca/dgv/app/home) were considered non-somatic variants and excluded. Results were analyzed with CNAG (v.3.0) 24 or Genotyping Console (Affymetrix). All other lesions were confirmed as somatic or germ-line by analysis of CD3-sorted cells. Sh...

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Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10

Cited by 80 publications

References 50 publications

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

BRCC3 mutations in myeloid neoplasms

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