Thymoquinone Inhibits Growth of Acute Myeloid Leukemia Cells through Reversal SHP-1 and SOCS-3 Hypermethylation: In Vitro and In Silico Evaluation

Epigenetic silencing of tumor suppressor genes (TSGs) plays an essential role in cancer pathogenesis, including acute myeloid leukemia (AML). All of SHP-1, SOCS-1, and SOCS-3 are TSGs that negatively regulate JAK/STAT signaling. Enhanced re-expression of TSGs through de-methylation represents a therapeutic target in several cancers. Thymoquinone (TQ) is a major component of Nigella sativa seeds with anticancer effects against several cancers. However, the effects of TQ on DNA methylation are not entirely understood. This study aimed to evaluate the ability of TQ to re-express SHP-1, SOCS-1, and SOCS-3 in MV4-11 AML cells through de-methylation. Cytotoxicity, apoptosis, and cell cycle assays were performed using WSTs-8 kit, Annexin V-FITC/PI apoptosis detection kit, and fluorometric-red cell cycle assay kit, respectively. The methylation of SHP-1, SOCS-1, and SOCS-3 was evaluated by pyrosequencing analysis. The expression of SHP-1, SOCS-1, SOCS-3, JAK2, STAT3, STAT5A, STAT5B, FLT3-ITD, DNMT1, DNMT3A, DNMT3B, TET2, and WT1 was assessed by RT-qPCR. The molecular docking of TQ to JAK2, STAT 3, and STAT5 was evaluated. The results revealed that TQ significantly inhibited the growth of MV4-11 cells and induced apoptosis in a dose- and time-dependent manner. Interestingly, the results showed that TQ binds the active pocket of JAK2, STAT3, and STAT5 to inhibit their enzymatic activity and significantly enhances the re-expression of SHP-1 and SOCS-3 through de-methylation. In conclusion, TQ curbs MV4-11 cells by inhibiting the enzymatic activity of JAK/STAT signaling through hypomethylation and re-expression of JAK/STAT negative regulators and could be a promising therapeutic candidate for AML patients.

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Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells

Blood ◽

10.1182/blood.v77.11.2404.2404 ◽

1991 ◽

Vol 77 (11) ◽

pp. 2404-2412 ◽

Cited By ~ 41

Author(s):

DC Roy ◽

JD Griffin ◽

M Belvin ◽

WA Blattler ◽

JM Lambert ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Bone Marrow Cells ◽

Leukemic Cells ◽

Short Exposure ◽

Continuous Exposure ◽

Dependent Manner ◽

Acute Myeloid

Abstract The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti- MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti- MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9- bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C′), Anti- MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU- GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.

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Results from the first-in-human study of mivebresib (ABBV-075), a pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7030 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7030-7030 ◽

Cited By ~ 5

Author(s):

Olatoyosi Odenike ◽

Johannes E. Wolff ◽

Gautam Borthakur ◽

Ibrahim Taha Aldoss ◽

David Rizzieri ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Febrile Neutropenia ◽

Myeloid Leukemia ◽

Target Genes ◽

Phase 1 ◽

Human Study ◽

Dependent Manner ◽

Bet Inhibitor ◽

Acute Myeloid

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.

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Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9

Blood ◽

10.1182/blood-2005-04-1679 ◽

2005 ◽

Vol 106 (13) ◽

pp. 4269-4277 ◽

Cited By ~ 27

Author(s):

Hiroyuki Kawagoe ◽

Gerard C. Grosveld

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Translocation ◽

Lymphoid Cells ◽

Dependent Manner ◽

Myeloproliferative Disease ◽

Long Latency ◽

Acute Myeloid

The chromosomal translocation t(12; 22)(p13;q11) in human myeloid leukemia generates an MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein. This protein consists of N-terminal MN1 sequences, a transcriptional coactivator fused to C-terminal TEL sequences, an ETS (E26 transformation-specific) transcription factor. Enforced expression of MN1-TEL in multipotent hematopoietic progenitors in knock-in mice perturbed growth and differentiation of myeloid as well as lymphoid cells. Depending on obligatory secondary mutations, these mice developed T-cell lympholeukemia. Here we addressed the role of MN1-TEL in myeloid leukemogenesis using the same mouse model. Expression of MN1-TEL enhanced the growth of myeloid progenitors in an interleukin 3/stem cell factor (IL-3/SCF)–dependent manner in vitro whereas 10% of MN1-TEL–expressing mice developed altered myelopoiesis with severe anemia after long latency. Coexpression of MN1-TEL and IL-3, but not SCF, rapidly caused a fatal myeloproliferative disease rather than acute myeloid leukemia (AML). Because MN1-TEL+ AML patient cells overexpress HOXA9 (homeobox A9), we tested the effect of coexpression of MN1-TEL and HOXA9 in mice and found that 90% of MN1-TEL+/HOXA9+ mice developed AML much more rapidly than control HOXA9+ mice. Thus, the leukemogenic effect of MN1-TEL in our knock-in mice is pleiotropic, and the type of secondary mutation determines disease outcome.

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Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9

Blood ◽

10.1182/blood.2019004586 ◽

2020 ◽

Author(s):

Seiko Yoshino ◽

Takashi Yokoyama ◽

Yoshitaka Sunami ◽

Tomoko Takahara ◽

Aya Nakamura ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Genetic Effect ◽

Dependent Manner ◽

Enhancer Activity ◽

Downstream Target ◽

Erk Phosphorylation ◽

Acute Myeloid

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPa and interacts with MEK1 to enhance ERK phosphorylation. Close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased mRNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPa p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

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Dentatin Induces Apoptosis and Cell Cycle Arrest of Acute Myeloid Leukemia Cells

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:52-57 ◽

2020 ◽

Vol 19 (1) ◽

pp. 52-57

Author(s):

Li Wen ◽

Yuli Liang ◽

Jing Li ◽

Meijie Quan ◽

Yanxiao Li ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Cell Viability ◽

Cell Apoptosis ◽

Myeloid Leukemia ◽

Cell Counting ◽

Dependent Manner ◽

Cycle Arrest ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

Acute myeloid leukemia remains a therapeutic challenge in the medical field and improvement in chemotherapeutics is needed. In this paper, MOLM-13 cells were treated with different concentrations (0, 10, 50, 100 µM) of dentatin and cell viability was detected using Cell Counting Kit-8. Cell cycle and cell apoptosis rates were evaluated by flow cytometry. The relevant proteins were assessed by Western blot. Consequently, the results show that dentatin inhibits the cell viability in a dose-dependent manner. In addition, dentatin arrests the cell cycle at G1 phase (P ‹ 0.01). Moreover, dentatin induces the cell apoptosis. Further study revealed that dentatin downregulates the phosphorylated STAT3 and CyclinD1 but upregulates the cleaved caspase-3. In summary, this study confirms that dentatin inhibits MOLM-13 cell viability, increases cell apoptosis, and retards cell cycle.

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Isocitrate Dehydrogenase Mutations Induce BCL-2 Dependence in Acute Myeloid Leukemia through Inhibition of Cytochrome C Oxidase Function

Blood ◽

10.1182/blood.v124.21.615.615 ◽

2014 ◽

Vol 124 (21) ◽

pp. 615-615

Author(s):

Steven M. Chan ◽

Daniel Thomas ◽

Bruno C Medeiros ◽

Ravindra Majeti

Keyword(s):

Acute Myeloid Leukemia ◽

Cytochrome C ◽

Enzymatic Activity ◽

Cytochrome C Oxidase ◽

Myeloid Leukemia ◽

Dependent Manner ◽

Synthetic Lethal ◽

Lethal Phenotype ◽

Idh Mutations ◽

Acute Myeloid

Abstract IDH1 and IDH2 are two of the most frequently mutated genes in acute myeloid leukemia at an overall frequency of about 15-20%. The genes encode enzymes in the citric acid cycle that normally catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (α-KG). The mutant enzymes gain a neomorphic activity that catalyzes the conversion of α-KG to (R)-2-hydroxyglutarate (2-HG). The intracellular concentration of (R)-2-HG is over 100-fold higher in IDH-mutated cells than in wildtype cells. (R)-2-HG has been shown to be a competitive inhibitor of multiple α-KG dependent dioxygenases including TET2, and the Jumonji-C domain containing histone demethylases. These enzymes are thought to be the main targets through which (R)-2-HG exerts its effects on leukemogenesis. We previously reported that inhibition of the anti-apoptotic BCL-2 protein is synthetic lethal against mutant IDH which we discovered through a large-scale pooled lentiviral RNA interference screen. We confirmed that expression of mutant IDH1 or IDH2 strikingly sensitized AML cells to shRNA-mediated BCL-2 knockdown and pharmacologic BCL-2 inhibition with ABT-199, a highly specific BH3 mimetic. Importantly, we found that primary human AML blasts harboring IDH mutations were significantly more sensitive to ABT-199 than blasts with wildtype IDH ex vivo and in xenograft transplant models. Furthermore, we showed that ABT-199 was able to target the leukemic stem cell compartment in IDH-mutated samples. Here, we present our work to uncover the synthetic lethal mechanism. An important clue to the mechanism surfaced with the finding that treatment with a cell-permeable precursor of (R)-2-HG sensitized AML cells to BCL-2 inhibition, indicating that the intracellular accumulation of (R)-2-HG found in IDH-mutated cells is sufficient to mediate the phenotype. In addition, we found that (R)-2-HG was able to sensitize isolated mitochondria to ABT-199 with collapse of the mitochondrial transmembrane potential as a surrogate marker for commitment to apoptosis. This finding indicates that 1) the target mediating the synthetic lethal phenotype is localized to the mitochondria, and 2) changes in the epigenome and expression of nuclear-encoded genes are not required for the synthetic lethal phenotype. To identify the potential mitochondrial molecular target, we focused our analysis on the effect of (R)-2-HG on the enzymatic activity of individual complexes in the electron transport chain (ETC), given that ETC dysfunction can potentially alter the threshold for apoptosis. We found that (R)-2-HG at concentrations found in IDH mutated cells inhibited the in vitro enzymatic activity of complex IV (cytochrome C oxidase (COX)) in a dose-dependent manner, but had no effect on the remaining ETC complexes. This finding has in vivo significance as COX activity in intact IDH-mutated primary AML cells was found to be significantly decreased compared with non-mutated AML cells. Next, we investigated the possibility that COX inhibition is sufficient to induce BCL-2 dependence. We found that suppression of COX activity with chemical inhibitors or genetically through shRNA-mediated knockdown of a COX subunit (COX-IV) was sufficient to sensitize AML cells to ABT-199. Furthermore, treatment with tigecycline, a FDA-approved antibiotic that has previously been shown to disrupt ETC function through inhibition of mitochondrial translation resulting in decreased expression of mitochondrial-encoded proteins including the catalytic subunits of the COX complex, reproduced the sensitization effect in non-IDH mutated AML cells. Based on the above findings, we propose a mechanistic model in which (R)-2-HG accumulation in IDH mutant cells directly inhibits COX, thereby lowering the mitochondrial threshold for triggering apoptosis upon BCL-2 inhibition. In summary, we discovered that in addition to the previously described inhibition of α-KG dependent dioxygenases through (R)-2-HG production, IDH mutations also affect mitochondrial bioenergetics. This finding opens up the intriguing possibility that IDH mutations contribute to leukemogenesis not only through epigenetic changes but also through metabolic dysregulation. Lastly, our findings form the rational basis for combining agents that disrupt ETC function such as tigecycline with ABT-199 to target resistant cancer cells and maximize the clinical utility of this promising drug. Disclosures Medeiros: Agios: Consulting - Ad board Other.

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Mesenchymal Stromal Cells Expressing Interferon α Limit the Development of Acute Myeloid Leukemia, Inducing Apoptosis In Vitro and In Vivo

Blood ◽

10.1182/blood.v128.22.5216.5216 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5216-5216

Author(s):

Laura M Desbourdes ◽

Adam J Guess ◽

Suheyla Hasgur ◽

Kathleen M Overholt ◽

Minjun Yu ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Stromal Cells ◽

Myeloid Leukemia ◽

Flow Cytometric Analysis ◽

Interferon Α ◽

Flow Cytometric ◽

Acute Myeloid

Abstract Introduction The 5-year survival for patients with acute myeloid leukemia (AML) has stagnated for over two decades at about 60% for children, 40% for young adults, and <15% for elderly patients. While most patients achieve remission, approximately 50% will relapse which is generally attributed to the persistence of leukemic stem cells. Interferon α (IFNα) is an effective therapy for patients with AML due to multiple mechanisms of action. However, high serum levels are associated with many adverse effects. In this proof-of-concept study, we used engineered mesenchymal stem/stromal cells (MSC) to deliver high concentrations of IFNα locally to an AML chloroma, potentially diminishing the poorly tolerated systemic side-effects. Methods Bone marrow MSCs from C57BL/6 mouse were isolated and transduced with a lentiviral vector expressing murine IFNα (IFNα-MSCs) and/or GFP (GFP MSCs). After measuring IFNα secretion by ELISA and confirming activity by the induction of the MHC I expression on the transduced cells, the anti-AML activity of these transduced MSCs was assessed by co-culture with the C57BL/6 AML cell line c1498 which expresses DsRed and firefly luciferase (FFluc). Apoptotic cell frequencies and cell cycle phase distributions of leukemia cells with or without MSCs were assessed by flow cytometry. The in vivo validation has been performed by subcutaneous injection of c1498 cells (chloroma) with or without GFP MSCs or IFNα MSCs in C57BL/6 mice. Tumor growth was monitored by bioluminescence imaging every 3 or 4 days. Results Flow cytometric analysis and ELISA confirmed the secretion of bio-active of IFNα by transduced MSCs (41.5 ng/1E06 MSCs/24h). In co-cultures, the presence of IFNα MSCs at the ratio 100:1 (c1498: MSC) significantly decreased the population of c1498 cells mainly by inducing apoptosis compared to MSC-free or GFP MSC co-cultures while no effect was observed on cell cycle distribution. The pro-apoptotic effect of IFNα MSCs was then investigated in vivo by subcutaneous injection of c1498 cells with or without MSCs (ratio 10:1) in C57BL/6 mice.The presence of IFNα MSCs significantly decreased leukemic cell mass as shown by the bioluminescence of the DsRed+ FFLuc+ c1498 cells. This result was confirmed by flow cytometric analysis of the percentage of DsRed + cells in the chloroma. Conclusions This study shows that IFNα MSCs present a strong anti-leukemic effect in vitro and in vivo promoting apoptosis and thus decreasing the leukemic burden. Further experiments will focus on a potential synergetic effect with Cytarabine treatment and a preclinical study using human IFNα MSCs in a xenograft murine model. Disclosures No relevant conflicts of interest to declare.

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Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro

Blood Advances ◽

10.1182/bloodadvances.2019001292 ◽

2020 ◽

Vol 4 (13) ◽

pp. 3000-3010 ◽

Cited By ~ 2

Author(s):

Jan Habbel ◽

Lucas Arnold ◽

Yiyang Chen ◽

Michael Möllmann ◽

Kirsten Bruderek ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Inflammatory Responses ◽

Janus Kinase ◽

Antileukemic Activity ◽

Hematopoietic Stem ◽

Stat Signaling ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Malignant niches frequently go along with inflammatory responses, but their impact on cancerogenesis often remains unexplored. Here, we uncovered an aberrant production of inflammatory cytokines in untreated AML bone marrow that was proved to promote the proliferation of leukemia cells. This inflammatory response induced an activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in AML blasts as well as bone marrow stromal cells that also fostered leukemia proliferation. Inhibition of JAK/STAT signaling using the selective JAK1/2 inhibitor ruxolitinib resulted in significant antileukemic activity in AML in vitro which is mediated through both cell-autonomous and microenvironment-mediated mechanisms. However, in a xenograft transplantation model, monotherapy with ruxolitinib did not achieve substantial antileukemic activity, possibly suggesting a complementary function of JAK1/2 inhibition in AML.

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Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.763232 ◽

2021 ◽

Vol 11 ◽

Author(s):

Mingyue Shi ◽

Junwei Niu ◽

Xiaona Niu ◽

Honggang Guo ◽

Yanliang Bai ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Cycle Progression ◽

Rna Binding ◽

Leukemic Cells ◽

Luciferase Reporter ◽

Rip Assay ◽

Acute Myeloid

The prognosis of chemoresistant acute myeloid leukemia (AML) is still poor, mainly owing to the sustained proliferation ability of leukemic cells, while the microtubules have a major role in sustaining the continuity of cell cycle. In the present study, we have identified CENPE, a microtubular kinesin-like motor protein that is highly expressed in the peripheral blood of patients with chemoresistant AML. In our in vitro studies, knockdown of CENPE expression resulted in the suppression of proliferation of myeloid leukemia cells and reversal of cytarabine (Ara-C) chemoresistance. Furthermore, Lin28A, one of the RNA-binding oncogene proteins that increase cell proliferation and invasion and contribute to unfavorable treatment responses in certain malignancies, was found to be remarkably correlated with CENPE expression in chemoresistance AML. Overexpression of LIN28A promoted the proliferation and Ara-C chemoresistance of leukemic cells. RIP assay, RNA pull-down, and dual luciferase reporter analyses indicated that LIN28A bound specifically to the promoter region GGAGA of CENPE. In addition, the impacts of LIN28A on cell growth, apoptosis, cell cycle progression, and Ara-C chemoresistance were reverted by the knockdown of CENPE. Hence, Lin28A/CENPE has enhanced the proliferation and chemoresistance of AML, and therefore, it could be a prospective candidate for AML treatment.

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The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

Biomedicines ◽

10.3390/biomedicines9081051 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1051

Author(s):

Bernhard Moser ◽

Sophie Edtmayer ◽

Agnieszka Witalisz-Siepracka ◽

Dagmar Stoiber

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Janus Kinase ◽

Hematopoietic Malignancy ◽

Stat Signaling ◽

Acute Myeloid ◽

Stat Pathway

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.

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