scholarly journals A novel imatinib-upregulated long noncoding RNA plays a critical role in inhibition of tumor growth induced by Abl oncogenes

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Yun Ma ◽  
Guijie Guo ◽  
Tingting Li ◽  
Faxin Wen ◽  
Jianling Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Growth ◽  
Cell Survival ◽  
Cellular Transformation ◽  
Leukemic Cells ◽  
Transformed Cell ◽  
Primary Bone ◽  
Primary Bone Marrow ◽  
Xenografted Tumor

Abstract Background Dysregulation of long noncoding RNAs (lncRNAs) has been linked to various human cancers. Bcr-Abl oncogene that results from a reciprocal translocation between human chromosome 9 and 22, is associated with several hematological malignancies. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Methods LncRNA cDNA microarray was employed to identify key lncRNAs involved in Bcr-Abl-mediated cellular transformation. Abl-transformed cell survival and xenografted tumor growth in mice were evaluated to dissect the role of imatinib-upregulated lncRNA 1 (IUR1) in Abl-induced tumorigenesis. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR1 knockout (KO) mice were further conducted to address the functional relevance of lncRNA-IUR1 in Abl-mediated leukemia. Transcriptome RNA-seq and Western blotting were performed to determine the mechanisms by which lncRNA-IUR1 regulates Bcr-Abl-induced tumorigenesis. Results We identified lncRNA-IUR1 as a critical negative regulator of Bcr-Abl-induced tumorigenesis. LncRNA-IUR1 expressed in a very low level in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, it was significantly induced in Abl-positive leukemic cells treated by imatinib. Depletion of lncRNA-IUR1 promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of lncRNA-IUR1 sensitized the cells to apoptosis and suppressed tumor growth. In concert, silencing murine lncRNA-IUR1 in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, lncRNA-IUR1 deficient mice were generated, and we observed that knockout of murine lncRNA-IUR1 facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA-IUR1 deficiency promoted Abl-transformed cell survival and development of leukemia in mice. Mechanistically, we demonstrated that lncRNA-IUR1 suppressed Bcr-Abl-induced tumorigenesis through negatively regulating STAT5-mediated GATA3 expression. Conclusions These findings unveil an inhibitory role of lncRNA-IUR1 in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis.

Selective Targeting Of Inv(16)+ AML Stem Progenitor Cells By Inhibiting HDAC8

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 224-224
Author(s):  
Jing Qi ◽  
Sandeep Singh ◽  
Qi Cai ◽  
Ling Li ◽  
Hongjun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Control Group ◽  
Cd34 Cells ◽  
Stem And Progenitor Cells ◽  
Primary Bone ◽  
Primary Bone Marrow ◽  
Acute Myeloid

Abstract Chromosomal inversion inv(16)(p13.1q22) which leads to the fusion of the transcription factor gene CBFb and the MYH11 gene, occurs in over 8% of acute myeloid leukemia (AML) cases. The fusion product CBFβ-SMMHC (CM) inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. The mutations of tumor suppressor p53 occur in approximately half of all cases of human cancer, but TP53 mutations are relatively rare in inv(16) AML. We have previously shown that CM expression leads to reduced acetylation of p53 and impaired p53 target gene activation through formation of aberrant protein complex with p53 and HDAC8 (Blood, 2012,120: A772.). Here, we showed that CM interacts with p53 both in CM transformed mouse primary bone marrow cells as well as in AML stem and progenitor cells from inv(16) patients. When HDAC8 selective pharmacological inhibitor 22d directed against its catalytic sites (ChemMedChem 2012, 7:10, 1815-24;) were used to treat inv(16) mouse primary bone marrow progenitor cells and inv(16)+ CD34+ stem progenitor cells from patients, Ac-p53 levels were remarkably increased as shown by western blot. We further assessed the p53 target genes expression after HDAC8 inhibitor 22d treatment by qRT-PCR assay in inv(16)+ CD34+ stem progenitor cells (n=8), and observed variable levels of activation in p53 targets (Fold activation: p21:2.25-fold, hdm2:1.17-fold, 14-3-3σ: 3.12-fold, puma: 2.39-fold), indicating p53 was re-activated. Similar results were also shown in CM transformed mouse bone marrow progenitor cells. Importantly, we found that 22d treatment significantly inhibit the growth of inv(16)+ AML CD34+ cells (n=9) rather than normal CD34+ cells (n=7) , (AML IC50= 6.509 μM, vs Normal cells IC50=13.83 μM, p=0.0003). Meanwhile, 22d selectively induces apoptosis of inv(16)+ AML stem and progenitor cells while sparing normal HSPCs (AML LD50= 10.24 μM, vs NL LD50= 46.36 μM, p=0.001). To evaluate whether the effect of HDAC8i is mediated by p53, we knocked down p53 with a lentiviral vector expressing shRNA against p53 (or non-silencing shRNA) in AML CD34+ cells, and treated the cells with HDAC8 inhibitor 22d (5-20 µM). We showed that despite the inter-sample variability, knocking down p53 expression in all AML samples tested (n=3) led to reduced HDAC8i-induced apoptosis, suggesting that p53 contributes to the apoptosis effect induced by HDAC8i (22d) in inv(16)+ AML cells. Importantly, by taking advantage of our conditional knock-in mouse model (Cbfb56M/+/Mx1-Cre), which develops AML under induced expression of CBFß-SMMHC (Cancer Cell, 2006, 9:1, 57-68), we were able to perform the ex vivo treatment assay by treating primary leukemic cells (marked with dTomato) with either DMSO (as vehicle control) or with HDAC8 inhibitor 22d (10μM) for 48h, followed by transplantion into congenic mice (control group n=8, treatment group n=7). We observed reduced short-term engraftment of leukemic cells that are treated with 22d (10 μM) at 4 weeks post-transplantation in the peripheral blood (Donor cell%: control group=5.99%, treatment group=0.178%, P=0.0093). Interestingly, engraftment of cord blood CD34+ cells at 16 weeks post-bone marrow transplantation was not reduced after treatment with 22d (10 μM) (human CD45+ %: control=66.2% versus treatment=63.4%, p=0.9), indicating the effect by HDAC8 inhibition is selective for leukemic cells. In conclusion, we have identified a novel mechanism whereby CBFβ-SMMHC inhibits p53 fucntion, and may further implicate inhibition of HDAC8 as a promising approach to selectively target inv(16)+ AML stem and progenitor cells. Disclosures: No relevant conflicts of interest to declare.

A proteomics approach to elucidate the role of Nrf2 in primary bone-marrow-derived dendritic cells of mice upon activation by contact allergens

2014 ◽  
Vol 229 ◽  
pp. S203
Author(s):  
Franz Mussotter ◽  
Andrea Haase ◽  
Janina Melanie Tomm ◽  
Zeina El Ali ◽  
Saadia Kerdine-Römer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Contact Allergens ◽  
Proteomics Approach ◽  
Primary Bone ◽  
Primary Bone Marrow

scholarly journals PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 164
Author(s):  
Federica Costa ◽  
Valentina Marchica ◽  
Paola Storti ◽  
Fabio Malavasi ◽  
Nicola Giuliani
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Survival ◽  
Immune Suppression ◽  
Metabolic Pathways ◽  
Therapeutic Strategy ◽  
Myeloma Cell ◽  
Immune Microenvironment ◽  
Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

scholarly journals Primary Bone Marrow B-Cell Lymphoma Undetected by Multiple Imaging Modalities That Initially Presented with Hypercalcemia

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Jin Sae Yoo ◽  
Juwon Kim ◽  
Hyeong Ju Kwon ◽  
Jung Soo Lim
Keyword(s):  
Computed Tomography ◽  
Bone Marrow ◽  
B Cell ◽  
Cell Lymphoma ◽  
Hematologic Malignancy ◽  
B Cell Lymphoma ◽  
Severe Hypercalcemia ◽  
Multiple Imaging ◽  
Primary Bone ◽  
Primary Bone Marrow

Purpose. We report a rare case of severe hypercalcemia that was ultimately diagnosed as primary bone marrow diffuse large B-cell lymphoma (BCL). Case Report. A 74-year-old male patient visited our hospital complaining of tenderness and swelling of the left knee caused by supracondylar fracture of the left distal femur. His initial blood tests showed a serum calcium level of 13.9 mg/dL, inorganic phosphorus of 4.34 mg/dL, and a serum creatinine level of 1.54 mg/dL. A serum assay of intact parathyroid hormone showed 5.24 pg/mL, and the patient’s serum 25(OH)D level was 22.33 ng/mL. To exclude malignancy, we performed imaging studies, including abdomen or chest computed tomography and positron emission tomography-computed tomography; however, no suspicious lesion was found, although the serum PTH-related peptide level was elevated at 4.0 pmol/L. A bone marrow biopsy was performed to identify any hidden hematologic malignancy. As a result, the pathology of bone marrow confirmed the presence of atypical lymphocytes that stained positive for the CD20 marker, which is consistent with BCL involving the bone marrow. Conclusion. This case highlights the importance of pursuing a thorough workup for rare underlying causes of hypercalcemia when parathyroid-related etiologies can be excluded.

Sign in / Sign up

Export Citation Format

Share Document