Role of Genetic Analysis in New Treatments of Acute Myeloid Leukemia

Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

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Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

Genes and Cells ◽

10.23868/201903007 ◽

2019 ◽

Vol XIV (1) ◽

Author(s):

A.M. Radzhabova ◽

S.V. Voloshin ◽

I.S. Martynkevich ◽

A.A. Kuzyaeva ◽

V.A. Shuvaev ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Course Of Disease ◽

Acute Myeloid

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Faculty Opinions recommendation of Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718326593.793493199 ◽

2014 ◽

Author(s):

Xiaoyan Jiang ◽

Katharina Rothe

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Myeloid Leukemia ◽

Growth Factor Receptor ◽

Leukemia Stem Cells ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00233-2 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yiyi Yao ◽

Fenglin Li ◽

Jiansong Huang ◽

Jie Jin ◽

Huafeng Wang

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chemotherapy Resistance ◽

Bone Marrow Microenvironment ◽

Cytotoxic Effects ◽

High Relapse Rate ◽

Underlying Mechanisms ◽

Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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Role of CD19 and specific KIT‐D816 on risk stratification refinement in t(8;21) acute myeloid leukemia induced with different cytarabine intensities

Cancer Medicine ◽

10.1002/cam4.3705 ◽

2020 ◽

Author(s):

Biao Wang ◽

Bin Yang ◽

Yun Ling ◽

Jihong Zhang ◽

Xiaoying Hua ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Myeloid Leukemia ◽

Acute Myeloid

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High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽

10.1186/s12885-021-08193-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jun Li ◽

Zheng Ge

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

Cell Function ◽

Adverse Outcomes ◽

High Expression ◽

Micro Rnas ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

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