Abstract:Background: Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an excessive number of immature lymphocytes, including immature precursors of both B- and T cells. ALL affects children more often than adults. Immature lymphocytes lead to arrested differentiation and proliferation of cells. Its conventional treatments involve medication with dexamethasone, vincristine, and other anticancer drugs. Although the current first-line drugs can achieve effective treatment, they still cannot preve… Show more
“…Since their discovery in the 1950s, glucocorticoids play an essential role in the treatment of ALL because of their ability to block cell-cycle progression and induce apoptosis in ALL cells. Many publications have reported a positive correlation between in vitro corticoid responses of leukemic lymphoblasts and in vivo responses to glucocorticoid monotherapy [ 11 ]. Among glucocorticoids, prednisolone has been the most commonly used drug in ALL therapy.…”
Prednisolone has been used frequently in the treatment of acute lymphoblastic leukemia. However, to overcome the challenges of the treatment, the development of additional therapies is of great importance. Small, non-protein-coding RNAs, namely, microRNAs (miRNAs), are critical epigenetic regulators with physiological and pathological importance. This study is aimed at determining the effects of miR-146a, miR-155, and miR-181a inhibition with their corresponding anti-miRs on both leukemic and healthy cells, individually and with prednisolone. Leukemic (SUP-B15) and healthy B-lymphocyte (NCI-BL 2171) cell lines were used in this study. A total of 12 experimental groups included individual and combinational silenced ALL-associated miRNAs (hsa-miR-155, hsa-miR-146a, and hsa-miR-181a) and their combination with prednisolone. Cytotoxicity, proliferation, cell cycle, and apoptosis analyses were performed by using WST-1, trypan blue, APC-BrdU, Annexin V, and JC-1 methods in each study group, respectively. To control the effectiveness of anti-miR transfection and prednisolone application, miRNA expression analysis was performed from all groups. Anti-miR application was effective on the viability, proliferation, cell cycle, and apoptosis of leukemia cells, and this effect was increased with prednisolone administration. In addition, this activity was found to be very low on healthy cells. In conclusion, anti-miR applications may have the potential for clinical use of adjuvant to or as an alternative to conventional therapies for childhood acute lymphoblastic leukemia.
“…Since their discovery in the 1950s, glucocorticoids play an essential role in the treatment of ALL because of their ability to block cell-cycle progression and induce apoptosis in ALL cells. Many publications have reported a positive correlation between in vitro corticoid responses of leukemic lymphoblasts and in vivo responses to glucocorticoid monotherapy [ 11 ]. Among glucocorticoids, prednisolone has been the most commonly used drug in ALL therapy.…”
Prednisolone has been used frequently in the treatment of acute lymphoblastic leukemia. However, to overcome the challenges of the treatment, the development of additional therapies is of great importance. Small, non-protein-coding RNAs, namely, microRNAs (miRNAs), are critical epigenetic regulators with physiological and pathological importance. This study is aimed at determining the effects of miR-146a, miR-155, and miR-181a inhibition with their corresponding anti-miRs on both leukemic and healthy cells, individually and with prednisolone. Leukemic (SUP-B15) and healthy B-lymphocyte (NCI-BL 2171) cell lines were used in this study. A total of 12 experimental groups included individual and combinational silenced ALL-associated miRNAs (hsa-miR-155, hsa-miR-146a, and hsa-miR-181a) and their combination with prednisolone. Cytotoxicity, proliferation, cell cycle, and apoptosis analyses were performed by using WST-1, trypan blue, APC-BrdU, Annexin V, and JC-1 methods in each study group, respectively. To control the effectiveness of anti-miR transfection and prednisolone application, miRNA expression analysis was performed from all groups. Anti-miR application was effective on the viability, proliferation, cell cycle, and apoptosis of leukemia cells, and this effect was increased with prednisolone administration. In addition, this activity was found to be very low on healthy cells. In conclusion, anti-miR applications may have the potential for clinical use of adjuvant to or as an alternative to conventional therapies for childhood acute lymphoblastic leukemia.
“…Details of the DEPs enriched in each pathway are shown in Supplementary Tables S5 – 7 . The results showed that all DEPs were significantly enriched in the Notch and autophagy pathways, which have been previously associated with the occurrence and development of ALL 16 , 17 . Figure 4 Gene ontology function enrichment analysis of the differentially expressed proteins (DEPs).…”
Section: Resultsmentioning
confidence: 61%
“…Additionally, Takam et al described a modulatory effect of the Notch pathway in B-ALL, with Notch pathway suppression leading to increased chemosensitivity of B-ALL cells 27 . Autophagy was also previously associated with the development of ALL 17 . Collectively, these findings suggest that the Notch signaling and autophagy pathways contribute to the progression of B-ALL.…”
We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p < 0.001). The areas under the curves of ADAM17 and ATG3 were 0.989 and 0.956, respectively, demonstrating their diagnostic potential. In conclusion, ADAM17 and ATG3 in plasma-derived exosomes may contribute to the progression of B-ALL by regulating the Notch and autophagy pathways. Hence, these proteins may represent valuable diagnostic biomarkers and therapeutic targets for B-ALL.
“…Recent studies suggest that inhibiting autophagy may be an efficient approach to improve the chemotherapeutic antileukemic regimens. Through suppressing autophagy in ETV6-RXNX1 gene positive B-ALL could severely downregulate cell proliferation and survival [52]. For example, an autophagy inhibitor, choloroquine, could increase the response of patients with B-ALL to the chemotherapy [53].…”
Section: Ocs and Leukemiamentioning
confidence: 99%
“…Furthermore, hydroxychloroquine, an autophagy inhibitor, reduces proliferation and survival of leukemic blasts in ALL [54]. Targeting suppressing autophagy in T-ALL was also effective and could be used to support further clinical trials in the future [52]. However, how secretory lysosomes in osteoclasts work still needs to be clarified.…”
Bone marrow microenvironment provides critical regulatory signals for lineage differentiation and maintenance of HSC quiescence, and these signals also contribute to hematological myeloid malignancies. Macrophages exhibit high phenotypic heterogeneity under both physiological and pathological conditions and are mainly divided into proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, osteoclasts are multinucleated giant cells that arise by fusion of monocyte/macrophage-like cells, which are commonly known as bone macrophages. Emerging evidence suggests that macrophages and osteoclasts originating from myeloid progenitors lead to two competing differentiation outcomes, and they appear to play an important role in the onset, progression, and bone metastasis of solid cancers. However, little is known about their role in the development of hematological malignancies. In this review, we focus on macrophages and osteoclasts, their role in leukemia, and the potential for targeting these cells in this disease.
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