Role of Autophagy and Apoptosis in Acute Lymphoblastic Leukemia

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 prevent the recurrence of some patients with ALL. Treatments have high risk of recurrence especially after the first remission. Currently, novel therapies to treat ALL are in need. Autophagy and apoptosis play important roles in regulating cancer development. Autophagy involves degradation of proteins and organelles, and apoptosis leads to cell death. These phenomena are crucial in cancer progression. Past studies reported that many potential anticancer agents regulate intracellular signaling pathways. Methods: The authors discuss the recent research findings on the role of autophagy and apoptosis in ALL. Results: The autophagy and apoptosis are widely used in the treatment of ALL. Most studies showed that many agents regulate autophagy and apoptosis in ALL cell models, clinical trials, and ALL animal models. Conclusions: In summary, activating autophagy and apoptosis pathways are the main strategies for ALL treatments. For ALL, combining new drugs with traditional chemotherapy and glucocorticoids treatments can achieve the greatest therapeutic effect by activating autophagy and apoptosis.

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The Treatment of Adults with Acute Lymphoblastic Leukemia

Hematology ◽

10.1182/asheducation-2008.1.381 ◽

2008 ◽

Vol 2008 (1) ◽

pp. 381-389 ◽

Cited By ~ 19

Author(s):

Adele Fielding

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Evidence Base ◽

Current Evidence ◽

Disease Biology ◽

Current Evidence Base ◽

Low Incidence ◽

Treat All

Abstract Despite the relatively low incidence of acute lymphoblastic leukemia (ALL) in adults, large national and international collaborations have recently improved our understanding of how to treat ALL in adults. This article documents and examines the current evidence base for a “state of the art” therapy in both Philadelphia chromosome–negative and –positive adult ALL. The article comments upon areas of therapeutic debate, such as the role of bone marrow transplantation. In particular, the controversial subject of whether the superior outcome seen in younger patients is predicated on disease biology or therapeutic strategy is examined closely. Promising approaches under development are also discussed.

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MicroRNAs and Their Role in Acute Lymphoblastic Leukemia

10.5772/intechopen.94960 ◽

2020 ◽

Author(s):

Edgardo Becerra Becerra ◽

Guadalupe García-Alcocer

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Transcriptional Level ◽

High Risk Disease ◽

Important Approach ◽

Treat All ◽

Differentiation And Proliferation ◽

Therapy Strategies

Acute lymphoblastic leukemia (ALL) has been established as the most common acute leukemia in children, accounting for 80–85% of cases. ALL occurs mostly in children and it is considered as a high-risk disease in the elderlies. ALL is characterized by a clonal disorder where the normal hematopoiesis is replaced by a malignant clonal expansion of lymphoid progenitors. Although many therapeutic strategies have been established to treat ALL leading to improved survival rates, the short-term and long-term complications derived from treatment toxicity represent a critical risk for patients. The treatment-related toxicity suggests a need for the development of new therapy strategies to effectively treat high-risk and low-risk disease. Nowadays, an important approach is focused on the identification of molecules involved in the mechanisms that lead to leukemia generation and progression to determine potential targets at the transcriptional level. MicroRNAs (miRNAs) are a group of key molecules that regulate signaling pathways related to lymphopoiesis. miRNAs participate in the regulation of hematopoietic differentiation and proliferation, as well as their activity. The present review details the recompilation of evidences about the relation between miRNAs and lymphopoiesis, ALL development and progression in order to propose and explore novel strategies to modulate ALL-related miRNA levels as a therapeutic approach.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽

10.3390/cells8091037 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1037 ◽

Cited By ~ 6

Author(s):

Cho ◽

Kim ◽

Baek ◽

Kim ◽

Lee

Keyword(s):

Cell Migration ◽

Cancer Progression ◽

Anticancer Agents ◽

Rho Gtpases ◽

Rho Gtpase ◽

Regulatory Mechanisms ◽

Malignant Phenotype ◽

Cellular Processes ◽

Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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The Role of Allogeneic Hematopoietic Stem Cell Transplantation in the Therapy of Patients with Acute Lymphoblastic Leukemia

Current Hematologic Malignancy Reports ◽

10.1007/s11899-012-0116-3 ◽

2012 ◽

Vol 7 (2) ◽

pp. 144-152 ◽

Cited By ~ 9

Author(s):

Partow Kebriaei ◽

L. M. Poon

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Lymphoblastic Leukemia ◽

Hematopoietic Stem

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The role of miRNA-196a2 genotypes in the susceptibility of acute lymphoblastic leukemia in Egyptian children

Gene Reports ◽

10.1016/j.genrep.2021.101237 ◽

2021 ◽

pp. 101237

Author(s):

N.A. Abdulhafeez ◽

D.M. Abd El Hassib ◽

O.M. Atef ◽

S.G. Ameen

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Egyptian Children

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Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽

10.3390/life11040365 ◽

2021 ◽

Vol 11 (4) ◽

pp. 365

Author(s):

Carina Colturato-Kido ◽

Rayssa M. Lopes ◽

Hyllana C. D. Medeiros ◽

Claudia A. Costa ◽

Laura F. L. Prado-Souza ◽

...

Keyword(s):

Cell Death ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Clinical Problem ◽

Jurkat Cells ◽

Leukemia Cells ◽

Peripheral Mononuclear Blood ◽

Induced Apoptosis ◽

Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

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