scholarly journals A switch toward demethylation is associated with the expression of myeloperoxidase in acute myeloblastic and promyelocytic leukemias

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2066-2073 ◽  
Author(s):  
M Lubbert ◽  
W Oster ◽  
WD Ludwig ◽  
A Ganser ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Specific Gene ◽  
Methylation Analysis ◽  
Myeloid Leukemias ◽  
Different Types ◽  
Genes Encoding ◽  
Specific Proteins

Abstract Expression of numerous genes encoding myeloid-specific proteins is tightly regulated during normal myeloid differentiation. This heterogeneous group of genes thus offers a tool for dissection of different maturational steps of myelopoiesis. We have previously shown that the human myeloperoxidase (MPO) gene is modified at numerous CpG residues in normal myeloid cells and in myeloid cell lines in a development-specific and expression-associated manner. In the present work, we have applied this type of methylation analysis to primary leukemia myeloid cell samples. We found that expression of MPO messenger RNA (mRNA) is grossly limited to leukemias of late myeloblastic and promyelocytic stages; expression is thus associated with progressive demethylation in the 5′ region of the MPO gene. This modification was not global. Low-level induction of MPO mRNA expression in very immature leukemic cells using phorbol ester was not accompanied by progressive demethylation. This type of methylation analysis of a myeloid-specific gene may yield a molecular indicator for different types of myeloid leukemias.

scholarly journals A switch toward demethylation is associated with the expression of myeloperoxidase in acute myeloblastic and promyelocytic leukemias

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2066-2073
Author(s):  
M Lubbert ◽  
W Oster ◽  
WD Ludwig ◽  
A Ganser ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Specific Gene ◽  
Methylation Analysis ◽  
Myeloid Leukemias ◽  
Different Types ◽  
Genes Encoding ◽  
Specific Proteins

Expression of numerous genes encoding myeloid-specific proteins is tightly regulated during normal myeloid differentiation. This heterogeneous group of genes thus offers a tool for dissection of different maturational steps of myelopoiesis. We have previously shown that the human myeloperoxidase (MPO) gene is modified at numerous CpG residues in normal myeloid cells and in myeloid cell lines in a development-specific and expression-associated manner. In the present work, we have applied this type of methylation analysis to primary leukemia myeloid cell samples. We found that expression of MPO messenger RNA (mRNA) is grossly limited to leukemias of late myeloblastic and promyelocytic stages; expression is thus associated with progressive demethylation in the 5′ region of the MPO gene. This modification was not global. Low-level induction of MPO mRNA expression in very immature leukemic cells using phorbol ester was not accompanied by progressive demethylation. This type of methylation analysis of a myeloid-specific gene may yield a molecular indicator for different types of myeloid leukemias.

scholarly journals Id2 expression increases with differentiation of human myeloid cells

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5225-5231 ◽  
Author(s):  
A Ishiguro ◽  
KS Spirin ◽  
M Shiohara ◽  
A Tobler ◽  
AF Gombart ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Northern Hybridization ◽  
Id Proteins ◽  
Normal Human

Id proteins are helix-loop-helix (HLH) transcriptional factors that lack the basic DNA binding domain. The Id proteins have been reported generally to function as inhibitors of cell differentiation, and their gene expression is often downregulated during cell differentiation. We examined the expression of human Id mRNAs by Northern hybridization in 11 human myeloid cell lines, several myeloid cell lines induced to differentiate, fresh myeloid leukemia samples, and normal human myeloid cells. Id2 mRNA was expressed in myelomonoblastic and monoblastic leukemic cells (PLB-985, THP-1, and U-937) but was weakly expressed in myeloblastic leukemic cells (KG-1 and HL-60). Id2 mRNA levels markedly increased with induction of differentiation of myeloid blasts (HL-60, PLB-985, THP-1, and U-937) toward either granulocytes or macrophages. Examination of fresh acute myeloid leukemic samples from 22 individuals also showed prominent Id2 mRNA expression in those samples having more differentiated blasts. Using the French-American-British classification, only 2 of 8 M0/M1 samples expressed Id2 mRNA; however, 10 of 13 M2/M3/M4 samples expressed it. In normal human myeloid cells, Id2 mRNA was expressed in cultured macrophages from bone marrow and in mature granulocytes and monocytes from peripheral blood. The half-life of Id2 mRNA was short (1 hour), and its expression was inducible by cessation of protein synthesis. Id3 mRNA was moderately expressed in monoblastic cell lines (THP-1 and U-937), and levels decreased with their differentiation. Almost no Id3 expression was detectable in either other myeloid leukemia lines, fresh leukemic samples, or normal human myeloid cells by Northern analyses. Id1 mRNA was not detected by polymerase chain reaction in either leukemic or normal myeloid cells except in K562 myeloid/erythroid cells. These results showed that Id2 mRNA was constitutively expressed in more mature myeloid blast cells and level markedly increased with terminal myeloid differentiation, suggesting that Id2 protein may inhibit an HLH transcriptional complex that normally represses myeloid differentiation.

scholarly journals Human myeloperoxidase gene expression in acute leukemia

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2096-2102 ◽  
Author(s):  
SR Zaki ◽  
GE Austin ◽  
D Swan ◽  
A Srinivasan ◽  
AH Ragab ◽  
...  
Keyword(s):  
Gene Expression ◽  
Early Stage ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Cdna Clones ◽  
Oligonucleotide Probes ◽  
Acute Leukemias ◽  
Normal Bone ◽  
Myeloid Leukemias ◽  
The Relationship

Abstract To evaluate the relationship between myeloperoxidase (MPO) gene expression and specific lineages of hematopoietic differentiation, we analyzed expression of the MPO gene in a variety of normal and leukemic human cells. As a first step, we synthesized several oligonucleotide probes and isolated cDNA clones for the MPO gene. MPO expression was detected in most acute myeloid leukemias, and the level of expression correlated well with cytochemical enzymatic activity. No MPO message was detected in pure lymphoid leukemias, whereas very low basal levels of MPO transcripts were found in normal bone marrows. In four cases of acute undifferentiated leukemias cytochemically negative for MPO, significant levels of MPO transcripts were detected, suggesting a myeloid origin for these cases. These results indicate that MPO gene expression may serve as an additional marker for subclassification of acute leukemias and may be used to identify leukemic cells arrested at an early stage of the myeloid differentiation pathway.

scholarly journals Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1938 ◽  
Author(s):  
Radhakrishnan Sridhar ◽  
Hisashi Takei ◽  
Riyaz Syed ◽  
Ikei Kobayashi ◽  
Liu Hui ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Granulocytic Differentiation ◽  
Leukemia Cell Lines ◽  
Expression Activity ◽  
Differentiation Marker ◽  
Neutrophil Differentiation

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.

scholarly journals Human myeloperoxidase gene expression in acute leukemia

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2096-2102
Author(s):  
SR Zaki ◽  
GE Austin ◽  
D Swan ◽  
A Srinivasan ◽  
AH Ragab ◽  
...  
Keyword(s):  
Gene Expression ◽  
Early Stage ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Cdna Clones ◽  
Oligonucleotide Probes ◽  
Acute Leukemias ◽  
Normal Bone ◽  
Myeloid Leukemias ◽  
The Relationship

To evaluate the relationship between myeloperoxidase (MPO) gene expression and specific lineages of hematopoietic differentiation, we analyzed expression of the MPO gene in a variety of normal and leukemic human cells. As a first step, we synthesized several oligonucleotide probes and isolated cDNA clones for the MPO gene. MPO expression was detected in most acute myeloid leukemias, and the level of expression correlated well with cytochemical enzymatic activity. No MPO message was detected in pure lymphoid leukemias, whereas very low basal levels of MPO transcripts were found in normal bone marrows. In four cases of acute undifferentiated leukemias cytochemically negative for MPO, significant levels of MPO transcripts were detected, suggesting a myeloid origin for these cases. These results indicate that MPO gene expression may serve as an additional marker for subclassification of acute leukemias and may be used to identify leukemic cells arrested at an early stage of the myeloid differentiation pathway.

Egr-1 Functions as a Tumor Suppressor for Leukemias Caused by Different Oncogenes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1450-1450
Author(s):  
John D. Gibbs ◽  
Dan A. Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Tumor Suppressor ◽  
Growth Arrest ◽  
Terminal Differentiation ◽  
Morphological Differentiation ◽  
Myeloid Cell ◽  
Intermediate Stage ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Differentiation Therapy ◽  
Molecular Nature

Abstract Deregulated expression of the proto-oncogenes c-myc, E2F-1 and c-myb in M1 myeloid leukemic cells rendered these cells incapable of undergoing myeloid terminal differentiation and its associated growth arrest, and prevented the loss in leukemogenicity normally observed when M1 cells are induced to differentiate. We recently showed that expressing Egr-1 in M1myc cells abrogated the c-myc-mediated block in terminal myeloid differentiation, with the cells undergoing macrophage maturation in the absence of growth arrest. Importantly, Egr-1 also abrogated c-myc-driven leukemogenicity. In this study, we asked if Egr-1 functions as a tumor suppressor by abrogating the block in differentiation caused by other oncogenes. It was shown that expressing Egr-1 in M1E2F-1 cells completely overrode the block in terminal myeloid cell differentiation, with the cells undergoing macrophage maturation, and unlike in myc/Egr-1 expressing cells, also becoming growth arrested. In contrast, expression of Egr-1 in M1myb cells promoted progression of the differentiation program to an intermediate stage of differentiation, but the cells became neither fully matured nor growth arrested, continuing to proliferate indefinitely. As seen for expression of Egr-1 in M1myc cells, Egr-1 expression in M1E2F-1 cells also abrogated E2F-1 driven leukemogenicity. In contrast, Egr-1 co-expression with c-myb in M1myb cells did not abrogate myb driven leukemia. Taken together, it can be concluded that Egr-1 is dominant to both E2F-1 and c-myc with regard to terminal morphological differentiation and the ability to suppress leukemias, whereas the proto-oncogene c-myb is dominant to Egr-1. These findings indicate that the tumor suppressor Egr-1 provides important tools for differentiation therapy of multiple leukemic phenotypes, dependent on the molecular nature of the activated oncogene.

scholarly journals Evidence for position effects as a variantETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13)

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1776-1784 ◽  
Author(s):  
Jan Cools ◽  
Nicole Mentens ◽  
Maria D. Odero ◽  
Pieter Peeters ◽  
Iwona Wlodarska ◽  
...  
Keyword(s):  
Molecular Level ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Fusion Genes ◽  
Position Effects ◽  
Fusion Transcripts ◽  
Myeloid Leukemias ◽  
Genes Encoding ◽  
Frame Fusion ◽  
Genomic Regions

The ETV6 gene (first identified as TEL) is a frequent target of chromosomal translocations in both myeloid and lymphoid leukemias. At present, more than 40 distinct translocations have been cytogenetically described, of which 13 have now also been characterized at the molecular level. These studies revealed the generation of in-frame fusion genes between different domains of ETV6 and partner genes encoding either kinases or transcription factors. However, in a number of cases—including a t(6;12)(q23;p13), the recurrent t(5;12)(q31;p13), and some cases of the t(4;12)(q11-q12;p13) described in this work—functionally significant fusions could not be identified, raising the question as to what leukemogenic mechanism is implicated in these cases. To investigate this, we have evaluated the genomic regions at 4q11-q12 and 5q31, telomeric to the breakpoints of the t(4;12)(q11-q12;p13) and t(5;12)(q31;p13). The homeobox geneGSH2 at 4q11-q12 and the IL-3/CSF2locus at 5q31 were found to be located close to the respective breakpoints. In addition, GSH2 and IL-3 were found to be ectopically expressed in the leukemic cells, suggesting that expression of GSH2 and IL-3 was deregulated by the translocation. Our results indicate that, besides the generation of fusion transcripts, deregulation of the expression of oncogenes could be a variant leukemogenic mechanism for translocations involving the 5′ end of ETV6, especially for those translocations lacking functionally significant fusion transcripts.

Gadd45a Behaves as a Tumor Suppressor and Gadd45b Behaves as an Oncogene in myc-Mediated Block in Myeloid Differentiation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4163-4163
Author(s):  
Alisha Mohamed-Hadley ◽  
John D. Gibbs ◽  
Dan A. Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Target Gene ◽  
Apoptotic Cell ◽  
Intermediate Stage ◽  
Leukemic Cells ◽  
Myeloid Differentiation ◽  
Wild Type ◽  
Apoptotic Pathway ◽  
Myeloid Leukemias

Abstract We have observed that deregulated c-Myc expression in M1 myeloid leukemic cells blocks IL-6-induced differentiation at an intermediate stage, the cells fail to exit the cell cycle, proliferating indefinitely, with a portion of the cells always undergoing apoptotic cell death by prematurely recruiting the CD95/Fas apoptotic pathway. Similar results were also observed in normal myeloid cells from bone marrow (Amanullah et al. Oncogene19:2967–77, 2000; Amanullah et al. Oncogene21:1600–1610, 2002). Although there is evidence that c-myc represses the gadd45a promoter, this laboratory has observed elevated gadd45a expression in M1myc cells that are blocked during differentiation. In addition, microarray analysis indicated that gadd45b is a c-myc target gene. Because of these observations and the availability of gadd45a null and gadd45b null mice, the effect of deregulated myc expression in Hoxb8 immortalized macrophage progenitors was ascertained. It was observed that deregulated c-myc expression in gadd45a null cells blocked differentiation at the blast stage, compared to a block at the intermediate stage for wild type progenitors. In contrast, deregulated c-myc expression in gadd45b null progenitors resulted in rapid cell death. These observations suggest that in the context of myc mediated myeloid leukemias Gadd45a behaves as a tumor suppressor and Gadd45b behaves as an oncogene.

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

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