Inhibition of Retinoic Acid Receptor Signaling by SKI in Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1132-1132
Author(s):  
Markus Ritter ◽  
Magnus Samuelsson ◽  
Oliver Hartmann ◽  
Andreas Burchert ◽  
Theo D. Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Real Time ◽  
Reporter Gene ◽  
Real Time Pcr ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Wild Type ◽  
Acute Myeloid

Abstract Objectives: Acute myeloid leukemia (AML) with monosomy 7 or deletion of the long arm of chromosome 7 (-7/7q-) is a leukemia with a poor outcome. Microarray analysis resulted in a gene expression profile specific for this subset of AML and showed SKI, a nuclear Co-repressor protein, being strongly upregulated. SKI is described to be a transforming gene, which inhibits TGF-beta-, SMAD- and retinoic acid (RA)-signaling. Materials, methods and patients: Gene expression profiling was performed using cDNA microarrays (detecting 4608 genes). Gene expression pattern of 20 AML (9 pts. with -7/7q- and 11 pts. with normal karyotype) patients was compared to 23 healthy bone marrow donors. Expression data of interestings genes were confirmed by real-time PCR in samples of 111 AML patients. In cell culture experiments HL60 and U937 leukemic cell lines were used to investigate the influence of the identified oncogene Ski on differentiating properties. In a reporter gene assay retinoic acid response element (RARE) was transfected in QT6 cells. U937 were retrovirally transfected with Ski wild type and Ski mutant. Results: Microarray analysis in AML (-7/7q-), revealed SKI being upregulated in AML. The group of patients with a high SKI expression level had a poorer overall survival when compared to the low expressers (p = 0.0279). Real-time PCR analysis comparing 111 AML samples to healthy CD34+ haematopoietic stem cells revealed, that SKI levels were highest in AML with -7/7q-, moderately elevated in most other karyotypes except AML with translocations involving retinoic acid receptor alpha (RARalpha). This suggests that Ski might interfere with RARalpha function in leukemia. Using reporter gene assays we could show that expression of wild-type, but not mutated SKI blocked RA induced differentiation. SKI was down regulated in HL60 leukemia cell line when differentiation was induced by ATRA and or valproic acid. Conclusion: Upregulation of SKI has prognostic significance in AML. Inhibition of RA signaling may be more often implicated in pathogenesis of AML than anticipated so far. The Co-repressor of histone deacetylases (HDACs) Ski might therefore become a molecular target for the induction of differentiation in the treatment of AML.

DNA methylation-independent loss of RARA gene expression in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2374-2377 ◽  
Author(s):  
Annegret Glasow ◽  
Angela Barrett ◽  
Kevin Petrie ◽  
Rajeev Gupta ◽  
Manuel Boix-Chornet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Positive Effects ◽  
All Trans Retinoic Acid ◽  
H3 Acetylation ◽  
Acute Myeloid

The retinoic acid receptor (RAR) α gene (RARA) encodes 2 major isoforms and mediates positive effects of all-trans retinoic acid (ATRA) on myelomonocytic differentiation. Expression of the ATRA-inducible (RARα2) isoform increases with myelomonocytic differentiation and appears to be down-regulated in many acute myeloid leukemia (AML) cell lines. Here, we demonstrate that relative to normal myeloid stem/progenitor cells, RARα2 expression is dramatically reduced in primary AML blasts. Expression of the RARα1 isoform is also significantly reduced in primary AML cells, but not in AML cell lines. Although the promoters directing expression of RARα1 and RARα2 are respectively unmethylated and methylated in AML cell lines, these regulatory regions are unmethylated in all the AML patient cell samples analyzed. Moreover, in primary AML cells, histones associated with the RARα2 promoter possessed diminished levels of H3 acetylation and lysine 4 methylation. These results underscore the complexities of the mechanisms responsible for deregulation of gene expression in AML and support the notion that diminished RARA expression contributes to leukemogenesis.

scholarly journals The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

2020 ◽  
Vol 295 (27) ◽  
pp. 8887-8900
Author(s):  
Nickolas Steinauer ◽  
Chun Guo ◽  
Jinsong Zhang
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Target Gene ◽  
Retinoic Acid Receptor ◽  
Inhibitory Effect ◽  
Myeloid Differentiation ◽  
Transcriptional Corepressor ◽  
Acute Myeloid

CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as MTG16 or ETO2) is a myeloid translocation gene family protein that functions as a master transcriptional corepressor in hematopoiesis. Recently, it has been shown that CBFA2T3 maintains leukemia stem cell gene expression and promotes relapse in acute myeloid leukemia (AML). However, a role for CBFA2T3 in myeloid differentiation of AML has not been reported. Here, we show that CBFA2T3 represses retinoic acid receptor (RAR) target gene expression and inhibits all-trans-retinoic acid (ATRA)-induced myeloid differentiation of AML cells. ChIP-Seq revealed that CBFA2T3 targets the RARα/RXRα cistrome in U937 AML cells, predominantly at myeloid-specific enhancers associated with terminal differentiation. CRISPR/Cas9-mediated abrogation of CBFA2T3 resulted in spontaneous and ATRA-induced activation of myeloid-specific genes in a manner correlated with myeloid differentiation. Importantly, these effects were reversed by CBFA2T3 re-expression. Mechanistic studies showed that CBFA2T3 inhibits RAR target gene transcription by acting at an early step to regulate histone acetyltransferase recruitment, histone acetylation, and chromatin accessibility at RARα target sites, independently of the downstream, RAR-mediated steps of transcription. Finally, we validated the inhibitory effect of CBFA2T3 on RAR in multiple AML subtypes and patient samples. To our knowledge, this is the first study to show that CBFA2T3 down-regulation is both necessary and sufficient for enhancing ATRA-induced myeloid gene expression and differentiation of AML cells. Our findings suggest that CBFA2T3 can serve as a potential target for enhancing AML responsiveness to ATRA differentiation therapies.

scholarly journals Acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration

2021 ◽  
Vol 12 ◽  
pp. 204062072097698
Author(s):  
Xiaoyan Han ◽  
Chunxiang Jin ◽  
Gaofeng Zheng ◽  
Yi Li ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Specific Factor ◽  
Acid Receptor ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Some subtypes of acute myeloid leukemia (AML) share morphologic, immunophenotypic, and clinical features of acute promyelocytic leukemia (APL), but lack a PML–RARA (promyelocytic leukemia–retinoic acid receptor alpha) fusion gene. Instead, they have the retinoic acid receptor beta (RARB) or retinoic acid receptor gamma (RARG) rearranged. Almost all of these AML subtypes exhibit resistance to all-trans retinoic acid (ATRA); undoubtedly, the prognosis is poor. Here, we present an AML patient resembling APL with a novel cleavage and polyadenylation specific factor 6 ( CPSF6) –RARG fusion, showing resistance to ATRA and poor response to chemotherapy with homoharringtonine and cytarabine. Simultaneously, the patient also had extramedullary infiltration.

scholarly journals ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3330-3338 ◽  
Author(s):  
Beatrice U. Mueller ◽  
Thomas Pabst ◽  
José Fos ◽  
Vibor Petkovic ◽  
Martin F. Fey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
All Trans Retinoic Acid ◽  
Conditional Expression ◽  
Neutrophil Differentiation ◽  
Acute Myeloid

Abstract Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor α (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).

scholarly journals Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4573-4585 ◽  
Author(s):  
Vernon T. Phan ◽  
David B. Shultz ◽  
Bao-Tran H. Truong ◽  
Timothy J. Blake ◽  
Anna L. Brown ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Cytokine Signaling ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Acute Myeloid

ABSTRACT We utilized a mouse model of acute promyelocytic leukemia (APL) to investigate how aberrant activation of cytokine signaling pathways interacts with chimeric transcription factors to generate acute myeloid leukemia. Expression in mice of the APL-associated fusion, PML-RARA, initially has only modest effects on myelopoiesis. Whereas treatment of control animals with interleukin-3 (IL-3) resulted in expanded myelopoiesis without a block in differentiation, PML-RARA abrogated differentiation that normally characterizes the response to IL-3. Retroviral transduction of bone marrow with an IL-3-expressing retrovirus revealed that IL-3 and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) combined to generate a lethal leukemia-like syndrome in <21 days. We also observed that a constitutively activated mutant IL-3 receptor, βcV449E, cooperated with PML-RARα in leukemogenesis, whereas a different activated mutant, βcI374N, did not. Analysis of additional mutations introduced into βcV449E showed that, although tyrosine phosphorylation of βc is necessary for cooperation, the Src homology 2 domain-containing transforming protein binding site is dispensable. Our results indicate that chimeric transcription factors can block the differentiative effects of growth factors. This combination can be potently leukemogenic, but the particular manner in which these types of mutations interact determines the ability of such combinations to generate acute myeloid leukemia.

Double, but Not Single, CEBPA mutations Define a Subgroup of Acute Myeloid Leukemia with Favorable Outcome and a Distinct Gene Expression Profile

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 141-141 ◽  
Author(s):  
Bas J. Wouters ◽  
Claudia A.J. Erpelinck-Verschueren ◽  
Bob Lowenberg ◽  
Peter J.M. Valk ◽  
Ruud Delwel
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Favorable Outcome ◽  
Heterozygous Mutation ◽  
Wild Type ◽  
Mutation Status ◽  
Cebpa Mutations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease characterized by various cytogenetic and molecular abnormalities, some of which can be used as prognostic markers. Mutations in the transcription factor CCAAT/enhancer binding protein alpha (CEBPA) occur in 5–10% of AML and have consistently been associated with a favorable outcome. Three types of mutations have been described: N-terminal out-of-frame mutations, inframe mutations in the basic leucine zipper (bZIP) region, and a small variable group of remaining aberrations. Most CEBPA mutant AML cases carry two mutations, usually on different alleles (double mutant). However, there are also cases that only express a single heterozygous mutation, and thus retain a wild type allele (single mutant). It is not known whether single and double CEBPA mutations should be considered of equal biological and/or clinical importance. We applied dHPLC WAVE technology in combination with nucleotide sequencing of the entire CEBPA gene in a cohort of 598 cases of adult de novo AML. After exclusion of previously described polymorphisms, we identified 41 cases (6.9%) with at least one mutation. Of these cases, 28 carried double mutations, i.e. two different heterozygous mutations or one homozygous mutation, whereas the remaining cases carried a single heterozygous mutation. To investigate whether CEBPA mutations were associated with specific transcriptional signatures, we examined genome-wide gene expression (GEP) data of 525/598 AMLs, including 38/41 CEBPA mutant cases. Class prediction of total CEBPA mutation status based on GEP data resulted in a relatively large number of false negatives in cross-validation using the PAM algorithm (sensitivity 68%, specificity 99%). Strikingly however, all these missed cases appeared to be of the single mutant group, while the double mutants were recognized with high accuracy. In agreement, unsupervised cluster analysis of the 525 AMLs led to distinct grouping of cases with double mutations, while cases with a single heterozygous mutation did not. These observations suggested that double and single CEBPA mutant AMLs represent distinct biological entities. We next assessed the clinical relevance of this finding. In concordance with previous studies, total CEBPA mutation status associated with favorable overall survival (OS) and event-free survival (EFS) (P=0.023 and P=0.042, log rank test), which was maintained in multivariable Cox’s proportional hazards models with cytogenetic risk group, FLT3-ITD and NPM1 mutation status, age and white blood cell count (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.29–0.77; P=0.002 and HR 0.52, 95% CI 0.33–0.82; P=0.004). Surprisingly, when the double and single CEBPA mutant cases were separately analyzed, only the double mutants showed a highly favorable outcome, while the single mutants could not be distinguished from CEBPA wild type AMLs (P=0.003 versus P=0.51 (OS) and P=0.004 versus P=0.18 (EFS)). In multivariable analysis, CEBPA double mutation status remained associated with favorable outcome (OS HR 0.31, 95% CI 0.16–0.59; P&lt;0.001, and EFS HR 0.34; 95% CI 0.19–0.61; P&lt;0.001), contrasting with the single mutants (HR 1.18, 95% CI 0.58–2.41; P=0.64 and HR 1.65, 95% CI 0.84–3.23; P=0.15). Similarly, in multivariable analysis in the selected normal karyotype subset (n=193), CEBPA double mutations, but not single mutations, were significantly associated with OS (P=0.026 versus P=0.24) and EFS (P=0.013 versus P=0.42). In conclusion, these data demonstrate the existence of distinct transcriptional and clinical characteristics of AML cases with double CEBPA mutations and imply that it is crucial to discriminate them from single mutants to identify those patients with a favorable prognosis.

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