scholarly journals ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia

Oncotarget ◽  
2017 ◽  
Vol 8 (61) ◽  
pp. 103626-103639 ◽  
Author(s):  
Carolina Yaeko Namasu ◽  
Christiane Katzerke ◽  
Daniela Bräuer-Hartmann ◽  
Alexander Arthur Wurm ◽  
Dennis Gerloff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Myeloid Differentiation ◽  
Favorable Prognostic Factor ◽  
Factor C ◽  
Acute Myeloid

ABR, a Novel Inducer Of Transcription Factor C/EBPα, Is Necessary For Myeloid Differentiation and a Prognostic Factor In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3814-3814
Author(s):  
Carolina Yaeko Namasu ◽  
Dennis Gerloff ◽  
Alexander Arthur Wurm ◽  
Daniela Braeuer-Hartmann ◽  
Jens-Uwe Hartmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Myeloid Differentiation ◽  
U937 Cells ◽  
Acute Myeloid

Abstract ABR (Active BCR-related) is the only protein in humans and mice closely homologous to BCR. BCR acts as a tumor suppressor in different cancers, such as chronic myeloid leukemia and meningiomas. A putative anti-oncogenic role of ABR has been shown in tumors of the central nervous system, such as medulloblastoma and astrocytomas, in which deletion of ABR was found. However, the role of ABR in hematopoiesis or leukemia remains unclear. We hypothesized that ABR might be important for myelopoiesis via increasing the expression of C/EBPα, a transcription factor known to be pivotal for myeloid differentiation and functionally impaired in acute myeloid leukemia (AML). In fact, we found that ABR expression is dramatically down-regulated (Figure 1, p=0.01) in bone marrow from AML patients (pts; n=63) compared to bone marrow (BM) mononuclear cells from healthy donors (n=3). In agreement with this finding, Abr is significantly increased during M-CSF and G-CSF-stimulated differentiation of primary wild type mouse BM cells (p<0.05). Additionally, we observe that ABR is necessary for monopoiesis induced by PMA (phorbol 12-myristate 13-acetate), since ABR knockdown in leukemic U937 cells results in a significant reduction of about 50% in the number of CD11b+ cells 48h after PMA treatment (p<0.05). Enforced ABR expression induces C/EBPα and its targets M-CSFR, G-CSFR and microRNA (miR)-223 in U937 cells (p<0.01). Moreover, we prove that ABR knockdown prevents induction of CEBPA, M-CSFR and G-CSFR during PMA-mediated differentiation (p<0.05). ABR overexpression blocks cell-cycle progression and down-regulates the known C/EBPα inhibitor E2F1 (p<0.01) in U937 cells, indicating the functional role of ABR as tumor suppressor. Those data suggest that ABR might induce CEBPA expression via inhibition of cell cycle activator E2F1. Finally, we are the first to identify ABR as a good prognostic factor in AML: patients with high ABR expression (median cut) survive significantly longer after allogeneic hematopoietic stem cell transplantation (Figure 2, p=0.04, log-rank test). Furthermore, high ABR expression associates with a low percentage of blasts in the peripheral blood (p=0.006) and high levels of antileukemic miR-181a (p<0.001). In conclusion, these data indicate that ABR, a novel inducer of C/EBPα, is necessary for myelopoiesis and a prognostic factor in AML. Raising ABR levels might be a goal for future therapeutics in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Transcription Factor PU.1 Controls a Reversible Differentiation Program in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3930-3930
Author(s):  
Mark D McKenzie ◽  
Margherita Ghisi ◽  
Luisa Cimmino ◽  
Michael Erlichster ◽  
Ethan P Oxley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Significant Loss ◽  
Polymorphonuclear Neutrophil ◽  
Myeloid Differentiation ◽  
Myeloid Lineage ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive malignancy characterized by clonal expansion of transformed myeloid precursors that fail to differentiate into mature cells. Since myeloid lineage maturation curbs self-renewal and is considered irreversible, engaging this process in AML is an attractive therapeutic strategy. Results: Normal myeloid differentiation requires the transcription factor PU.1 (SPI1), which is functionally compromised in several AML subtypes and is directly inhibited by the recurrent fusion oncoproteins AML1-ETO and PML-RARA. To examine the importance of PU.1 suppression in AML maintenance in vivo, we have combined RNAi-mediated PU.1 inhibition with p53 deficiency to drive highly aggressive AML in mice. Using these models we find that restoring endogenous PU.1 activity in established AML in vivo is sufficient to trigger robust transcriptional, immunophenotypic, and morphological differentiation of leukemic blasts, yielding polymorphonuclear, neutrophil-like cells. Maturation of AML is associated with significant loss of cell viability and yields sustained disease clearance in vivo. Although PU.1 restoration is potently anti-leukemic, remarkably we find that subsequent suppression of PU.1 in mature neutrophil-like cells reverts them to a transformed state within several days. While mature AML-derived cells are slower to form blast colonies in methylcellulose cultures, their clonogenic frequency is only reduced four-fold relative to AML blasts suggesting highly efficient de-differentiation. Conclusions: These results demonstrate that triggering myeloid differentiation can effectively resolve a p53-deficient model of treatment resistant AML, but also identify a previously unrecognised ability of AML cells to bidirectionally transition between transformed and differentiated states based on the activity of a single transcription factor. Our findings challenge the concept of 'terminal differentiation' in AML and highlight the importance of therapeutically eradicating leukemia cells at all stages of myeloid lineage maturation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Activation of C/EBPa Myeloid-Specific Transcription Factor By NAMPT/SIRT1-Triggered Deacetylation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2199-2199
Author(s):  
Bardia Samareh ◽  
Masoud Nasri ◽  
Inna Zimmer ◽  
Olga Klimenkova ◽  
Leonie Keller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Myeloid Differentiation ◽  
Granulocytic Differentiation ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Previously, we described new mechanism of G-CSF-triggered granulocytic differentiation of hematopoietic stem cells (HSCs) via activation of the enzyme Nicotinamide Phosphorybosyltransferase (NAMPT) leading to NAD+ production and activation of NAD+ -dependent protein deacetylase sirtuin 1 (SIRT1). We found, that upon stimulation of HSCs with NAMPT, SIRT1 bound to the key myeloid transcription factor C/EBPα followed by transcriptional induction of C/EBPα target genes G-CSFR and G-CSF and granulocytic differentiation. In the present work we investigated the mechanism of NAMPT/SIRT1-triggered deacetylation of C/EBPα. We found that C/EBPα is acetylated at the position Lys 161, which is evolutionarily conserved. Lys 161 is localized in the transactivation element III (TE-III) of the transactivation domain (TAD) of C/EBPα protein, which is responsible for recruitment of SWI/SNF and CDK2/CDK4. Western blot and DUOLINK analysis using rabbit polyclonal antibody specifically recognizing acetyl-Lys 161 of C/EBPα revealed predominantly nuclear localization of acetylated C/EBPα protein in acute myeloid leukemia cell lines NB4 and HL60 as well as in primary HSCs. Induction of myeloid differentiation of HSCs by treatment with G-CSF as well as ATRA-induced differentiation of NB4 cells resulted in the deacetylation of C/EBPα. NAMPT inhibition in NB4 and HL60 cell lines using specific inhibitor FK866 led to the dramatically elevated levels of acetylated C/EBPα and reduced amounts of total C/EBPα protein, which was in line with diminished mRNA expression of C/EBPα target genes (G-CSF, G-CSFR and ELANE). Interestingly, treatment of acute myeloid leukemia cell line HL60 with NAMPT or transduction of HL-60 cells with NAMPT-expressing lentiviral construct induced myeloid differentiation of these cells even without addition of ATRA. This was in line with time- and dose-dependent increase of total C/EBPα protein levels upon NAMPT treatment. Therefore, NAMPT overcomes transcriptional repression of C/EBPα in HL-60 cells by activation of positive CEBPA autoregulation. Taken together, we described a new mechanism of regulation of C/EBPα activities in hematopoiesis and leukemogenesis by its post-translational modification via NAMPT/SIRT1-triggered de-/acetylation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Lianzhong Zhao ◽  
Pengcheng Zhang ◽  
Phillip M Galbo ◽  
Xinyue Zhou ◽  
Sajesan Aryal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemia Cell ◽  
Myeloid Differentiation ◽  
Growth Defect ◽  
Strong Negative Correlation ◽  
Acute Myeloid

Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a super-enhancer-associated, highly expressed gene in MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.

scholarly journals Lymphoid enhancer-binding factor 1 (LEF-1): a favorable prognostic factor in adult acute myeloid leukemia in Egyptian patients

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Botheina Ahmed Thabet Farweez ◽  
Nahela Ahmed Shalaby ◽  
Doaa Ahmed Gamal Eissa ◽  
Raghda El Sayed Abdel Monem Galal ◽  
Nashwa El-khazragy ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Binding Factor ◽  
Egyptian Patients ◽  
Favorable Prognostic Factor ◽  
Acute Myeloid

Lack of CD34 Expression in Acute Myeloid Leukemia (AML) Is a Favorable Prognostic Factor in Patients Treated with Stem Cell Transplant Irrespective of the Cytogenetic Risk

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1894-1894
Author(s):  
Fahed Almhareb ◽  
Claudia Ulrike Walter ◽  
Randa Nounou ◽  
Salem Khalil ◽  
Nasir Bakshi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Mutation Status ◽  
Allogeneic Hsct ◽  
Predicting Outcome ◽  
Favorable Prognostic Factor ◽  
Cd34 Expression ◽  
Acute Myeloid

Abstract Abstract 1894 Background: Most of the studies of prognostic factors in acute myeloid leukemia (AML) are focused on predicting outcome after standard chemotherapy treatment. The studies that looked at the importance of these prognostic variables in predicting outcome after hematopoietic stem cell transplantation (HSCT) are very limited. Considering post-HSCT prognostic factors in stratifying AML patients may add a new level of confidence in any risk stratification of these patients. Toward this goal, we investigated the clinical relevance of CD34 expression in the primary leukemic cells on the outcome of allogeneic HSCT. Methods: Data collected from immunophenotyping of 110 patients with AML who were treated with HSCT was reviewed and the expression of CD34 on the blast population as determined by flow cytometry was correlated with clinical behavior and outcome. All the patients were treated with allogeneic HSCT. The median age of these patients was 24 (range: 14–57) and included 88 patients in the intermediate cytogenetic group and 22 in the adverse cytogenetic group. Of the 110 patients 71, (64.5%) were treated with HSCT in first remission (CR1). Results: Twenty-eight (25%) of all AML patients studied did not express CD34 on the surface of the blasts at diagnosis. Patients with CD34 negative blasts had significantly longer overall survival (OS) (P=0.003) as well as longer event free survival (EFS) (P=0.01) when all patients were considered. In the subgroup of patients who received HSCT in CR1, OS and EFS were significantly longer (P=0.017 and P=0.027, respectively) in the CD34-negative patients (N=20). Furthermore, if we consider only patients in the intermediate cytogenetic group at diagnosis, patients with CD34-negative blasts had significantly longer OS (P=0.007) and EFS (P=0.026). Even in patients with adverse cytogenetic abnormalities, OS and EFS were also significantly longer in the CD34-negative patients (P=0.01 for both). This was true when all patients were considered. The same was true when only patients transplanted in CR1 (P=0.05 for EFS in intermediate cytogenetics and P=0.05 for EFS in patients with adverse cytogenetic) were evaluated. Multivariate analysis including CD34 expression and FLT3 mutation status was carried out on a subset of patients (N=63) and showed CD34 expression was an independent prognostic factor for survival and EFS, while FLT3 mutation status became no longer a predictor. Conclusion: Our data suggests that CD34 expression on the blast cells at the time of AML diagnosis may have an adverse prognostic impact even after allogeneic HSCT. Lack of CD34 expression is a powerful independent favorable prognostic factor for AML patients if these patients are treated with HSCT after induction chemotherapy, irrespective if they were in CR1 or in CR2, and irrespective of their cytogenetic risk at diagnosis. Disclosures: No relevant conflicts of interest to declare.

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