scholarly journals The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3173-3180 ◽  
Author(s):  
T Shimamoto ◽  
K Ohyashiki ◽  
JH Ohyashiki ◽  
K Kawakubo ◽  
T Fujimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Transcription Factors ◽  
Expression Pattern ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Cell Leukemia ◽  
Stem Cell Leukemia ◽  
Acute Myeloid

To understand the clinical implications of transcription factors and their biologic roles during cellular differentiation in the hematopoietic system, we examined the expression of GATA-1, GATA-2, and stem cell leukemia (SCL) gene in human leukemia cell lines and various leukemia patients using the reverse transcriptase-polymerase chain reaction. Cell lines exhibiting megakaryocytic or erythrocytic phenotypes had GATA-1, GATA-2, and SCL gene transcripts, while monocytic cell lines had no detectable GATA-1, GATA-2, or SCL gene mRNA. In some myeloid cell lines, GATA-1 expression, but not SCL gene expression, was detected; GATA-1 expression in HL-60 cells was downregulated during the process of monocytic differentiation. We next examined GATA-1, GATA-2, and SCL gene expression in 110 leukemia samples obtained from 76 patients with acute myeloid leukemia (AML), 19 with acute lymphoblastic leukemia (ALL), and 15 with chronic myeloid leukemia in blast crisis (CML-BC). SCL gene expression was usually accompanied by GATA-1 expression and was preferentially detected in patients with leukemia exhibiting megakaryocytic or erythrocytic phenotypes, while patients with monocytic leukemia were clustered in the group with no detectable GATA-1 expression. None of the patients with ALL or CML-lymphoid-BC expressed SCL. De novo AML patients with SCL gene expression had a lower complete remission (CR) rate and had a significantly poorer prognosis. Among the patients with AML not expressing SCL, a high percentage of patients with CD7+ AML and CD19+ AML had detectable GATA-1, while patients with GATA-1-negative AML had the best CR rate (87.5%). Our results suggest that the expression pattern of transcription factors reflects the lineage potential of leukemia cells, and GATA-1 and SCL gene expression may have prognostic value for the outcome of patients with AML.

scholarly journals The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3173-3180 ◽  
Author(s):  
T Shimamoto ◽  
K Ohyashiki ◽  
JH Ohyashiki ◽  
K Kawakubo ◽  
T Fujimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Transcription Factors ◽  
Expression Pattern ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Cell Leukemia ◽  
Stem Cell Leukemia ◽  
Acute Myeloid

Abstract To understand the clinical implications of transcription factors and their biologic roles during cellular differentiation in the hematopoietic system, we examined the expression of GATA-1, GATA-2, and stem cell leukemia (SCL) gene in human leukemia cell lines and various leukemia patients using the reverse transcriptase-polymerase chain reaction. Cell lines exhibiting megakaryocytic or erythrocytic phenotypes had GATA-1, GATA-2, and SCL gene transcripts, while monocytic cell lines had no detectable GATA-1, GATA-2, or SCL gene mRNA. In some myeloid cell lines, GATA-1 expression, but not SCL gene expression, was detected; GATA-1 expression in HL-60 cells was downregulated during the process of monocytic differentiation. We next examined GATA-1, GATA-2, and SCL gene expression in 110 leukemia samples obtained from 76 patients with acute myeloid leukemia (AML), 19 with acute lymphoblastic leukemia (ALL), and 15 with chronic myeloid leukemia in blast crisis (CML-BC). SCL gene expression was usually accompanied by GATA-1 expression and was preferentially detected in patients with leukemia exhibiting megakaryocytic or erythrocytic phenotypes, while patients with monocytic leukemia were clustered in the group with no detectable GATA-1 expression. None of the patients with ALL or CML-lymphoid-BC expressed SCL. De novo AML patients with SCL gene expression had a lower complete remission (CR) rate and had a significantly poorer prognosis. Among the patients with AML not expressing SCL, a high percentage of patients with CD7+ AML and CD19+ AML had detectable GATA-1, while patients with GATA-1-negative AML had the best CR rate (87.5%). Our results suggest that the expression pattern of transcription factors reflects the lineage potential of leukemia cells, and GATA-1 and SCL gene expression may have prognostic value for the outcome of patients with AML.

scholarly journals Ecotropic virus integration site-1 gene preferentially expressed in post-myelodysplasia acute myeloid leukemia: possible association with GATA-1, GATA-2, and stem cell leukemia gene expression

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3713-3718 ◽  
Author(s):  
JH Ohyashiki ◽  
K Ohyashiki ◽  
T Shimamoto ◽  
K Kawakubo ◽  
T Fujimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Integration Site ◽  
Cell Leukemia ◽  
Virus Integration ◽  
Ecotropic Virus ◽  
Stem Cell Leukemia ◽  
Acute Myeloid ◽  
Virus Integration Site

We investigated expression of the human ecotropic virus integration site-1 (EVI1) gene in patients with leukemia and myelodysplastic syndrome (MDS) using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. The EVI1 transcripts were detected in 5 (10.0%) of 50 patients with de novo acute myeloid leukemia (AML), including two AML patients with trilineage myelodysplasia, and in 8 (34.8%) of 23 patients with post-myelodysplastic syndrome AML (post-MDS AML). EVI1 expression was also detected in 6 (35.3%) of 17 MDS patients and three of six patients with chronic myeloid leukemia (CML) in myelomegakaryoblast crisis. No EVI1 transcripts were detected in patients with acute lymphoid leukemia (n = 15) or CML in lymphoid blast crisis (n = 4). Chromosomal abnormalities at the 3q26 region, where the EVI1 gene is located, were found in one patient with MDS and two patients with CML myelomegakaryoblast crisis who had EVI1 expression. Our results showed that EVI1 expression was frequent in patients with post-MDS AML and AML with trilineage myelodysplasia, regardless of the presence or absence of 3q26 abnormalities. EVI1 expression was accompanied by expression of GATA-1 and GATA-2, and often by stem cell leukemia (SCL) gene expression. In patients with post-MDS AML, EVI1 expression was not always associated with a 3q26 abnormality, whereas EVI1 expression in CML myelomegakaryoblast crisis was often linked to a 3q26 abnormality. Our results suggest that the leukemogenic role of EVI1 expression may differ between post-MDS AML and leukemia, with EVI1 expression associated with a 3q26 abnormality.

The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 348-357 ◽  
Author(s):  
Nicolas Duployez ◽  
Alice Marceau-Renaut ◽  
Céline Villenet ◽  
Arnaud Petit ◽  
Alexandra Rousseau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Gene Expression Signature ◽  
Pediatric Acute Myeloid Leukemia ◽  
Expression Signature ◽  
Acute Myeloid

scholarly journals Rewiring of the Transcription Factor Network in Acute Myeloid Leukemia

2019 ◽  
Vol 18 ◽  
pp. 117693511985986 ◽  
Author(s):  
Salam A Assi ◽  
Constanze Bonifer ◽  
Peter N Cockerill
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Myeloid Leukemia ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Genes Encoding ◽  
Myeloid Development ◽  
Mitogen Activated Protein ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a highly heterogeneous cancer associated with different patterns of gene expression determined by the nature of their DNA mutations. These mutations mostly act to deregulate gene expression by various mechanisms at the level of the nucleus. By performing genome-wide epigenetic profiling of cis-regulatory elements, we found that AML encompasses different mutation-specific subclasses associated with the rewiring of the gene regulatory networks that drive differentiation into different directions away from normal myeloid development. By integrating epigenetic profiles with gene expression and chromatin conformation data, we defined pathways within gene regulation networks that were differentially rewired within each mutation-specific subclass of AML. This analysis revealed 2 major classes of AML: one class defined by mutations in signaling molecules that activate AP-1 via the mitogen-activated protein (MAP) kinase pathway and a second class defined by mutations within genes encoding transcription factors such as RUNX1/CBFβ and C/EBPα. By identifying specific DNA motifs protected from DNase I digestion at cis-regulatory elements, we were able to infer candidate transcription factors bound to these motifs. These integrated analyses allowed the identification of AML subtype-specific core regulatory networks that are required for AML development and maintenance, which could now be targeted in personalized therapies.

scholarly journals All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Chi Huu Nguyen ◽  
Katharina Bauer ◽  
Hubert Hackl ◽  
Angela Schlerka ◽  
Elisabeth Koller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

AbstractEcotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

Pemetrexed Treatment of Breast Relapse in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4018-4018
Author(s):  
Chunyan Wang ◽  
Huo Tan ◽  
SiDa Peng ◽  
ZhenQian Huang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Side Effects ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Review Of The Literature ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Extramedullary Relapse ◽  
Acute Myeloid

Abstract Extramedullary relapse is a pattern of acute myeloid leukemia (AML) relapse post-allogeneic hematopoietic stem cell transplantation (alloHSCT). We present the case of a 43-year-old female patient with acute mix cell leukemia who had isolated extramedullary relapse develop in both breasts 2 years after alloHSCT, the first reported case in adult patients in the literature to the best of our knowledge. She received further chemotherapy with pemetrexed (Alimta) intravenous injection (500mg/D1, every 3 weeks is one course of treatment). After 2 courses of treatments, her swelled breasts were shrunk remarkably and no obvious side effects were found. We therefore conclude that pemetrexed treatment may be an effective regimen for breast extramedullary leukemia. Review of the literature about extramedullary relapse and breast involvement as well as the treatment of these cases were further discussed.

Deregulated Apoptotic Pathways Point to Effectiveness of IAP Inhibitor Therapy in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1275-1275
Author(s):  
Sonja C Lück ◽  
Annika C Russ ◽  
Konstanze Döhner ◽  
Ursula Botzenhardt ◽  
Domagoj Vucic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Cell Line ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Gene Set Enrichment Analysis ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Acute Myeloid

Abstract Abstract 1275 Poster Board I-297 Core binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the core binding factor, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, 40-50% of patients relapse, and the current classification system does not fully reflect the heterogeneity existing within the cytogenetic subgroups. Therefore, illuminating the biological mechanisms underlying these differences is important for an optimization of therapy. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences (Bullinger et al., Blood 2007). In order to further characterize these GEP defined CBF subgroups, we again used gene expression profiles to identify cell line models similar to the respective CBF cohorts. Treatment of these cell lines with cytarabine (araC) revealed a differential response to the drug as expected based on the expression patterns reflecting the CBF subgroups. In accordance, the cell lines resembling the inferior outcome CBF cohort (ME-1, MONO-MAC-1, OCI-AML2) were less sensitive to araC than those modeling the good prognostic subgroup (Kasumi-1, HEL, MV4-11). A previous gene set enrichment analysis had identified the pathways Caspase cascade in apoptosis and Role of mitochondria in apoptotic signaling among the most significant differentially regulated BioCarta pathways distinguishing the two CBF leukemia subgroups. Thus, we concluded that those pathways might be interesting targets for specific intervention, as deregulated apoptosis underlying the distinct subgroups should also result in a subgroup specific sensitivity to apoptotic stimuli. Therefore, we treated our model cell lines with the Smac mimetic BV6, which antagonizes inhibitor of apoptosis (IAP) proteins that are differentially expressed among our CBF cohorts. In general, sensitivity to BV6 treatment was higher in the cell lines corresponding to the subgroup with good outcome. Time-course experiments with the CBF leukemia cell line Kasumi-1 suggested a role for caspases in this response. Interestingly, combination treatment of araC and BV6 in Kasumi-1 showed a synergistic effect of these drugs, with the underlying mechanisms being currently further investigated. Based on the promising sensitivity to BV6 treatment in some cell lines, we next treated mononuclear cells (mostly leukemic blasts) derived from newly diagnosed AML patients with BV6 in vitro to evaluate BV6 potency in primary leukemia samples. Interestingly, in vitro BV6 treatment also discriminated AML cases into two distinct populations. Most patient samples were sensitive to BV6 monotherapy, but about one-third of cases were resistant even at higher BV6 dosage. GEP of BV6 sensitive patients (at 24h following either BV6 or DMSO treatment) provided insights into BV6-induced pathway alterations in the primary AML patient samples, which included apoptosis-related pathways. In contrast to the BV6 sensitive patients, GEP analyses of BV6 resistant cases revealed no differential regulation of apoptosis-related pathways in this cohort. These results provide evidence that targeting deregulated apoptosis pathways by Smac mimetics might represent a promising new therapeutic approach in AML and that GEP might be used to predict response to therapy, thereby enabling novel individual risk-adapted therapeutic approaches. Disclosures Vucic: Genentech, Inc.: Employment. Deshayes:Genentech, Inc.: Employment.

MiR-132 and MiR-212 as Regulators of WT1 and GATA2 in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1283-1283 ◽  
Author(s):  
Maaike Luesink ◽  
Jeannet Nigten ◽  
Ruth H.J.N. Knops ◽  
Theo J.M. de Witte ◽  
Bert A. van der Reijden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Quantitative Pcr ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Granulocytic Differentiation ◽  
Aberrant Expression ◽  
Differentiation Induction ◽  
Acute Myeloid

Abstract Abstract 1283 Poster Board I-305 Wilms' tumor 1 (WT1) and GATA binding protein 2 (GATA2) transcription factors are highly expressed in hematopoietic stem cells and progenitors. Differentiation of precursor blood cells towards mature blood cells is accompanied by rapid downregulation of both transcription factors. Overexpression of WT1 has been observed in the majority of acute myeloid leukemia (AML) cases. Furthermore, in 10-15% of the AML cases mutations in the WT1 gene occur, which have been correlated with poor prognosis. Aberrant expression of GATA2 in AML has been described as well, but no mutations in this gene have been reported in AML so far. How the (aberrant) expression of WT1 and GATA2 is controlled is not completely clear. A regulatory role for microRNAs (miRNAs) has been described for several transcription factors which regulate hematopoiesis. MiRNAs negatively regulate gene expression by translational repression or degradation of target messenger RNAs (mRNAs). In the present study we investigated the interplay between miRNAs and transcription factors that are involved in myeloid development and malignant transformation towards AML. We studied the expression of 158 miRNAs in the APL cell line NB4 during induction of granulocytic differentiation with all-trans retinoic acid (ATRA). Quantitative PCR specific for mature miRNAs was performed (Applied Biosystems). Twenty out of 158 miRNAs were more than 10-fold upregulated upon differentiation induction with ATRA. MiR-132 and miR212, which are derived from the same pri-miRNA transcript, were most strongly upregulated during ATRA-induced granulocytic differentiation (1200- and 350-fold respectively at 96 hours after ATRA-stimulation). In vitro ATRA-induction of primary APL cells also resulted in upregulation of miR-132 and miR-212. Computational target prediction algorithms were used to identify transcription factors which may be targeted by miR-132 and miR-212. Subsequently, the expression pattern of the predicted targets was determined experimentally in NB4 cells before and after differentiation induction with ATRA using microarray-based mRNA profiling (Affymetrix). In addition, further verification of target gene expression during ATRA-induced differentiation was performed using quantitative PCR. The transcription factors WT1 and GATA2 were predicted as targets of miR-132 and miR-212 by two out of four different prediction programs that were used. Both transcription factors contained putative binding sites for miR-132 and miR-212 in their 3'UTR. When tested on microarray and by quantitative PCR, the expression of WT1 and GATA2 was indeed strongly downregulated during ATRA-induced granulocytic differentiation of NB4 cells (65- and 165-fold respectively at 96 hours after ATRA stimulation) as well as in primary leukemia cells derived from APL patients (30- and 10-fold respectively at 48 hours after ATRA-stimulation). During ATRA-induced differentiation the expression levels of WT1 were positively correlated with the expression levels of GATA2. In addition, WT1 expression was also strongly correlated with GATA2 expression in a cohort of 27 pre-treatment AML cases as well as in 7 healthy controls, suggesting that these genes might be co-regulated to a large extent. To directly prove that WT1 and GATA2 are indeed targeted by miR-132 and miR-212, we are currently performing lentiviral-based overexpression studies of both miRNAs to determine the effect on endogenous WT1 and GATA2 mRNA expression. MicroRNAs which target WT1 and GATA2 may be valuable tools in controlling the aberrant expression of WT1 and GATA2 observed in AML. Disclosures No relevant conflicts of interest to declare.

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