GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations

Sportoletti, Paolo; Celani, Letizia; Varasano, Emanuela; Rossi, Roberta; Sorcini, Daniele; Rompietti, Chiara; Strozzini, Francesca; Papa, Beatrice Del; Guarente, Valerio; Spinozzi, Giulio; Cecchini, Debora; Bereshchenko, Oxana; Haferlach, Torsten; Martelli, Maria Paola; Falzetti, Franca; Falini, Brunangelo

doi:10.1038/s41375-019-0399-7

Cited by 14 publications

(15 citation statements)

References 15 publications

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“…To determine responsible factors further upstream of the presented glycomics data, we investigated amongst other potential candidates hematopoietic TFs. Based on current literature suggesting their involvement in AML pathobiology [ 47 , 48 , 49 , 50 ], we included TAL1 , GATA1-3 , SPI1 , CEPBA, and CBFA2T3 . Correlation of N - and O -glycan features with these TFs was assessed by regularized canonical correlation analysis (rCCA, Figure 5 , Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines

Blöchl

Wang

Madunić

et al. 2021

Cells

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Acute myeloid leukemia (AML) is characterized by a dysregulated expansion of poorly differentiated myeloid cells. Although patients are usually treated effectively by chemotherapy, a high rate of relapsed or refractory disease poses a major hurdle in its treatment. Recently, several studies have proposed implications of protein glycosylation in the pathobiology of AML including chemoresistance. Accordingly, associations have been found between specific glycan epitopes and the outcome of the disease. To advance this poorly studied field, we performed an exploratory glycomics study characterizing 21 widely used AML cell lines. Exploiting the benefits of porous graphitized carbon chromatography coupled to tandem mass spectrometry (PGC nano-LC-MS2), we qualitatively and quantitatively profiled N- and O-linked glycans. AML cell lines exhibited distinct glycan fingerprints differing in relevant glycan traits correlating with their cellular phenotype as classified by the FAB system. By implementing transcriptomics data, specific glycosyltransferases and hematopoietic transcription factors were identified, which are candidate drivers of the glycan phenotype of these cells. In conclusion, we report the varying expression of glycan structures across a high number of AML cell lines, including those associated with poor prognosis, identified underlying glycosyltransferases and transcription factors, and provide insights into the regulation of the AML glycan repertoire.

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Section: Resultsmentioning

confidence: 99%

Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines

Blöchl

Wang

Madunić

et al. 2021

Cells

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“…Specifically, Gata1 was one of the most upregulated genes in leukemic mice compared to the other genotypes whereas Gata2 was downregulated. The latter finding is unexpected since in physiological conditions [44], the transcription factor Gata2 is highly expressed in hematopoietic stem cells, whereas its expression declines after erythroid commitment of progenitors [43]. In contrast, the start of Gata1 expression coincides with the erythroid commitment and increases along with the erythroid differentiation.…”

Section: Discussionmentioning

confidence: 96%

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

et al. 2020

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Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor−/− knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor−/−/Dnmt3a−/− knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.

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“…Protein & Cell encodes a death-promoting transcriptional repressor and can regulate the differentiation of normal hematopoietic progenitors and is deregulated in AML (Dell'Aversana et al, 2017). Nucleophosmin 1 (NPM1) is frequently mutated in AML and exerts multifunctions in the regulation of centrosome duplication, ribosome biogenesis, genomic stability, histone chaperone function, and transcription (Verhaak et al, 2005;Heath et al, 2017); GATA binding protein 1 (GATA1) is a DNA-sequence specific TF which regulates erythroid development by controlling the fetal-to-adult hemoglobin switch, and correlates with the degree of myeloid phenotypic changes in Npm1/Flt3-ITD mice (Sportoletti et al, 2019). The results presented here suggest a previously unrecognized mechanism by which ASXL1 forms partnerships with many DNA-binding transcription regulators including TFs and guides the BAP1-containing PR-DUB complex to specific loci in the genome.…”

Section: Research Articlementioning

confidence: 99%

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

et al. 2020

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Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,

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GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations

Cited by 14 publications

References 15 publications

Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines

Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network

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