scholarly journals STAT3β is a tumor suppressor in acute myeloid leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1989-2002 ◽  
Author(s):  
Petra Aigner ◽  
Tatsuaki Mizutani ◽  
Jaqueline Horvath ◽  
Thomas Eder ◽  
Stefan Heber ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Dominant Negative ◽  
Expression Ratio ◽  
Mrna Ratio ◽  
Dominant Negative Form ◽  
Alternatively Spliced ◽  
Regulatory Functions ◽  
Acute Myeloid

Abstract Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9–dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML.

scholarly journals High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1517-1524 ◽  
Author(s):  
Marjan J. T. Veuger ◽  
M. Willy Honders ◽  
Jim E. Landegent ◽  
Roel Willemze ◽  
Renée M. Y. Barge
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Deoxycytidine Kinase ◽  
Wild Type ◽  
Healthy Donors ◽  
Alternatively Spliced ◽  
Acute Myeloid

Deficiency of functional deoxycytidine kinase (dCK) is a common characteristic for in vitro resistance to cytarabine (AraC). To investigate whether dCK is also a target for induction of AraC resistance in patients with acute myeloid leukemia (AML), we determined dCK messenger RNA (mRNA) expression in (purified) leukemic blasts and phytohemagglutinin-stimulated T cells (PHA T cells) from patients with chemotherapy-sensitive and chemotherapy-resistant AML. In control samples from healthy donors (PHA T cells and bone marrow), only wild-type dCK complementary DNA (cDNA) was amplified. Also, in (purified) leukemic blasts from patients with sensitive AML, only wild-type dCK cDNAs were observed. These cDNAs coded for active dCK proteins in vitro. However, in 7 of 12 (purified) leukemic blast samples from patients with resistant AML, additional polymerase chain reaction fragments with a deletion of exon 5, exons 3 to 4, exons 3 to 6, or exons 2 to 6 were detected in coexpression with wild-type dCK. Deletion of exons 3 to 6 was also identified in 6 of 12 PHA T cells generated from the patients with resistant AML. The deleted dCK mRNAs were formed by alternative splicing and did code for inactive dCK proteins in vitro. These findings suggest that the presence of inactive, alternatively spliced dCK mRNA transcripts in resistant AML blasts may contribute to the process of AraC resistance in patients with AML.

scholarly journals High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1517-1524 ◽  
Author(s):  
Marjan J. T. Veuger ◽  
M. Willy Honders ◽  
Jim E. Landegent ◽  
Roel Willemze ◽  
Renée M. Y. Barge
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Deoxycytidine Kinase ◽  
Wild Type ◽  
Healthy Donors ◽  
Alternatively Spliced ◽  
Acute Myeloid

Abstract Deficiency of functional deoxycytidine kinase (dCK) is a common characteristic for in vitro resistance to cytarabine (AraC). To investigate whether dCK is also a target for induction of AraC resistance in patients with acute myeloid leukemia (AML), we determined dCK messenger RNA (mRNA) expression in (purified) leukemic blasts and phytohemagglutinin-stimulated T cells (PHA T cells) from patients with chemotherapy-sensitive and chemotherapy-resistant AML. In control samples from healthy donors (PHA T cells and bone marrow), only wild-type dCK complementary DNA (cDNA) was amplified. Also, in (purified) leukemic blasts from patients with sensitive AML, only wild-type dCK cDNAs were observed. These cDNAs coded for active dCK proteins in vitro. However, in 7 of 12 (purified) leukemic blast samples from patients with resistant AML, additional polymerase chain reaction fragments with a deletion of exon 5, exons 3 to 4, exons 3 to 6, or exons 2 to 6 were detected in coexpression with wild-type dCK. Deletion of exons 3 to 6 was also identified in 6 of 12 PHA T cells generated from the patients with resistant AML. The deleted dCK mRNAs were formed by alternative splicing and did code for inactive dCK proteins in vitro. These findings suggest that the presence of inactive, alternatively spliced dCK mRNA transcripts in resistant AML blasts may contribute to the process of AraC resistance in patients with AML.

scholarly journals Functional implications of microRNAs in acute myeloid leukemia by integrating microRNA and messenger RNA expression profiling

Cancer ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 4696-4706 ◽  
Author(s):  
Violaine Havelange ◽  
Nicole Stauffer ◽  
Catherine C. E. Heaphy ◽  
Stefano Volinia ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Expression Profiling ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Rna Expression ◽  
Functional Implications ◽  
Rna Expression Profiling ◽  
Acute Myeloid

scholarly journals Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia

2017 ◽  
Vol 1 (20) ◽  
pp. 1682-1693 ◽  
Author(s):  
Ikuko Nakamae ◽  
Jun-ya Kato ◽  
Takashi Yokoyama ◽  
Hidenori Ito ◽  
Noriko Yoneda-Kato
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Expression Ratio ◽  
Human Patient ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Protein Levels ◽  
Acute Myeloid ◽  
Myeloid Progenitors

Abstract C/EBPα is a key transcription factor regulating myeloid differentiation and leukemogenesis. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPα for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPα protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPα for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocyte-macrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPα. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPα stability in the early phases of hematopoiesis and leukemogenesis.

ABI-1, a Human Homolog to Mouse Abl-Interactor 1, Fuses theMLL Gene in Acute Myeloid Leukemia With t(10;11)(p11.2;q23)

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1125-1130 ◽  
Author(s):  
Tomohiko Taki ◽  
Noriko Shibuya ◽  
Masafumi Taniwaki ◽  
Ryoji Hanada ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Sh3 Domain ◽  
Full Length ◽  
Homologous Region ◽  
Homeotic Genes ◽  
Human Homolog ◽  
Normal Peripheral Blood ◽  
Alternatively Spliced ◽  
Acute Myeloid

Abstract Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) andCALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes asrc homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL. © 1998 by The American Society of Hematology.

Acute Myeloid Leukemia with Deletion 9q Is Associated with CEBPA Loss-of-Function Mutations.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2896-2896
Author(s):  
Stefan Frohling ◽  
Richard F. Schlenk ◽  
Jurgen Krauter ◽  
Arnold Ganser ◽  
Christian Thiede ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Good Prognosis ◽  
Dominant Negative ◽  
Binding Potential ◽  
Complex Karyotype ◽  
Loss Of Function ◽  
Cebpa Mutations ◽  
Acute Myeloid

Abstract The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) plays an important role in the development of mature neutrophils. Two common types of mutations in the CEBPA gene encoding C/EBPalpha have been identified in approximately 10% of adults with acute myeloid leukemia (AML): N-terminal, dominant-negative frameshift mutations that result in loss of C/EBPalpha function and C-terminal in-frame mutations that result in C/EBPalpha proteins with decreased DNA-binding potential. Previous studies concluded that mutant CEBPA predicts favorable outcome in younger AML patients with intermediate-risk karyotypes or normal cytogenetics. To assess the prevalence of CEBPA mutations in specific cytogenetic subgroups, mutational analysis of the CEBPA gene was performed in 125 AML patients. No CEBPA mutations were detected in 77 patients with t(8;21), inv(16)/t(16;16), t(15;17), or balanced translocations with breakpoints in band 11q23. In 58 patients with various non-complex karyotypic abnormalities, CEBPA mutations were present in 8 (14%). Surprisingly, 5 of the 8 patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of C/EBPalpha function. Consequently, 41 additional del(9q) cases were analyzed; 9 had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) within a non-complex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) within a complex karyotype (n = 7), in combination with a t(8;21) (n = 10), or together with a t(15;17) (n = 1) demonstrated mutant CEBPA. Analysis of associated mutations indicated that alterations of the FLT3, MLL, and NRAS genes are not common cooperating events in the pathogenesis of del(9q) AML with inactivating CEBPA mutations. This is the first study to show that AML with del(9q) is strongly associated with CEBPA loss-of-function mutations. The coincidence of del(9q) with inactivating CEBPA mutations and the fact that del(9q) is a common secondary cytogenetic abnormality in t(8;21)-positive AML, that is characterized by specific down-regulation of CEBPA, raise the possibility that loss of a critical segment of 9q, most likely in 9q22, and disruption of C/EBPalpha function cooperate in the pathogenesis of these leukemias. Further refinement of the commonly deleted segment of 9q using high-resolution techniques is underway to identify the critical gene(s) involved and their role in normal hematopoiesis and leukemogenesis. A collaborative intergroup study has been initiated to define whether the relatively good prognosis associated with del(9q) is related to the presence of a CEBPA mutation.

The Critical Role of Peptidyl-Prolyl cis/trans Isomerase, Pin1 in Acute Myeloid Leukemia with C/EBPalpha Mutations.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2213-2213
Author(s):  
J. Pulikkan ◽  
A. Peer Zada ◽  
M. Geletu ◽  
V. Dengler ◽  
Daniel G. Tenen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dominant Negative ◽  
Pcr Analysis ◽  
Wild Type ◽  
Rt Pcr ◽  
Promoter Assay ◽  
Type C ◽  
Acute Myeloid

Abstract CCAAT enhancer binding protein alpha (C/EBPα) is a myeloid specific transcription factor that coordinates cellular differentiation and cell cycle arrest. Loss of C/EBPα expression or function in leukemic blasts contributes to a block in myeloid cell differentiation. C/EBPα is mutated in around 9% of acute myeloid leukemia (AML). The mutations reported in C/EBPα are frame shift mutations and point mutations at basic region Leucine zipper. The mutant form of C/EBPα ie C/EBPα-p30 exhibits dominant negative function over the wild type protein. The role of peptidyl-prolyl cis/trans isomerase, Pin1 in tumorogenesis and its overexpression in many cancers led us to investigate its role in acute myeloid leukemia with C/EBPα mutation. Here we show that Pin1 is upregulated in patients with acute myeloid leukemia by affymetrix analysis. By quantitative Real-Time RT-PCR analysis, we show C/EBPα-p30 could induce Pin1 transcription, while the wild type C/EBPα downregulates Pin1 expression. Luciferase promoter assay for the Pin1 promoter shows that wild type C/EBPα is able to block Pin1 promoter activity. Mean while, C/EBPα-p30 couldn’t block Pin1 promotor activity. By silencing Pin1 by RNA Interference as well as with inhibitor against Pin1 (PiB) we could show myeloid differentiation in human CD34+ cord blood cells as well as in Kasumi-6 cells as assessed by FACS analysis with granulocytic markers. We investigated the mechanism underlying the dominant negative action of C/EBPα-p30 over the wild type protein. We report that Pin1 increases the transcriptional activity of the oncogene c-jun. We also show that c-jun blocks the DNA binding and transactivation of C/EBPα protein as assessed by gel shift assay and promoter assay respectively. We have previously shown that c-jun expression is high in AML patients with C/EBPα mutation and c-jun could block C/EBPα function by protein-protein interaction. Quantitative Real-Time RT-PCR analysis shows that inhibition of Pin1 by the inhibitor PiB downregulates c-jun mRNA expression. In conclusion, inhibition of Pin1 leads to granulocytic differentiation. Our results show Pin1 as a novel target in treating AML patients with C/EBPα mutation.

Altered Regulation of Imprinted Non-Coding RNA Genes in Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3456-3456 ◽  
Author(s):  
Ming-Yu Yang ◽  
Jan-Gowth Chang ◽  
Pai-Mei Lin ◽  
Jui-Feng Hsu ◽  
Cheng-Han Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Imprinted Genes ◽  
Healthy Individuals ◽  
Regulatory Functions ◽  
Acute Myeloid

Abstract Abstract 3456 Studies in large-scale genome sequencing have shown that only 2% of the mammalian genome encodes mRNAs, but the most part is transcribed as long and short non-coding RNAs (ncRNAs). The ncRNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation. Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Imprinted genes tend to occur in clusters and ncRNAs have been found at all well-characterized imprinted clusters. Although the exact mechanism how imprinted ncRNA regulates gene expression remains largely unknown, it is general accepted that imprinted ncRNAs binds to chromatin modifying complexes, such as PRC2, TRX, and G9a, and generates specific silencing of genomic loci both in cis and trans. Imprinting is associated with many human diseases or syndromes (e.g. Prader-Willi, Angelman, Beckwith-Wiedemann, Retts, and Silver-Russell syndromes) and various cancers (e.g. breast, prostate, and colorectal cancers), but its role in leukemogenesis remain elusive. In this present study, a panel of 24 human imprinted ncRNAs genes, including ampd3, cpa4, snuf, rasgrf1, slc22a3, lgf2, treb3c, gabrb3, c15orf2, sfmbt2, rtl1, copg2, h19, l3mbtl, ppp1r9a, tspan32, lnpp5f, impact, nr3251, nr3252, znf215, prim2, peg3as and znf264, has been mined using Bioinformatics approach. We investigated the expression of these imprinted ncRNA genes using real-time quantitative RT-PCR in 67 newly-diagnosed acute myeloid leukemia patients with normal karyotypes (AML-NK), 22 AML patients with abnormal karyotypes (AML-AK), and 39 healthy individuals. In AML-NK patients, the expression of lgf2, h19, slc22a3, copg2, and impact were significantly upregulated than in healthy individuals (p < 0.0001). In AML-AK patients, besides lgf2, h19 and impact genes, ampd3 and gabrb3 were also significantly upregulated than in healthy individuals (p < 0.0001). Expression of igf2 was almost undetectable in healthy individuals but drastically increased in all AML patients. Both lgf2 and h19 were significantly increased in both AML-NK and AML-AK patients. From our preliminary results, it is reasonable to hypothesize that loss imprinting of lgf2/h19 is critical for the leukemogenesis of AML and under NK or AK conditions different additional ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform methylation analysis of promoter CpG sites in AML patients to investigate if hypomethylation is responsible for the upregulation of these imprinted ncRNAs. We will also carry out in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analysis will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

ABI-1, a Human Homolog to Mouse Abl-Interactor 1, Fuses theMLL Gene in Acute Myeloid Leukemia With t(10;11)(p11.2;q23)

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1125-1130 ◽  
Author(s):  
Tomohiko Taki ◽  
Noriko Shibuya ◽  
Masafumi Taniwaki ◽  
Ryoji Hanada ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Sh3 Domain ◽  
Full Length ◽  
Homologous Region ◽  
Homeotic Genes ◽  
Human Homolog ◽  
Normal Peripheral Blood ◽  
Alternatively Spliced ◽  
Acute Myeloid

Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) andCALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes asrc homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL. © 1998 by The American Society of Hematology.

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