Leukemia Stem Cells in the Pathogenesis, Progression, and Treatment of Acute Myeloid Leukemia

Joshi, Kanak; Zhang, Lei; J, Peter Breslin S; Zhang, Jiwang

doi:10.1007/978-981-13-7342-8_5

Cited by 3 publications

(3 citation statements)

References 256 publications

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“…Next-generation DNA/RNA sequence assays showed a dynamic accumulation of driver mutations during the development and progression of hematopoietic malignancies. It was suggested that the average number of driver mutations is increased from 1 in ARCH to 3 in MDS and > 5 in AML [22,23,165]. Single-cell approaches, including single-cell DNA-seq, single-cell RNA-seq, and single-cell proteomics, demonstrated a clonal heterogeneity in the architecture of these hematopoietic malignancies due to both linear and branching clonal evolutionary processes in disease development.…”

Section: Clonally Heterogenic Architecture Of Hematopoietic Malignanciesmentioning

confidence: 99%

“…Moreover, the clonal architectures in different patients are different. Thus, the dynamic and heterogenic clonal evolutionary processes occurring in these malignancies make the diseases difficult to treat [165]. Therefore, understanding the unique biology of each clone by elucidating how the concurrent mutations collaborate in the induction, development, and progression of the disease will suggest novel combinatory strategies for eventually curing these fatal diseases.…”

Section: Clonally Heterogenic Architecture Of Hematopoietic Malignanciesmentioning

confidence: 99%

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Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Joshi

Zhang²,

S.J.³

et al. 2022

J Exp Clin Cancer Res

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The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40–50% of cases of TET2-mutant (TET2MT) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2MT collaborates with co-occurring mutations to promote malignant transformation. In TET2MT tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2MT hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2MT malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2MT hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals.

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Section: Clonally Heterogenic Architecture Of Hematopoietic Malignanciesmentioning

confidence: 99%

Section: Clonally Heterogenic Architecture Of Hematopoietic Malignanciesmentioning

confidence: 99%

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Joshi

Zhang²,

S.J.³

et al. 2022

J Exp Clin Cancer Res

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“…Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal diseases that originated from hematopoietic stem cells and are characterized by pathological hematopoiesis of blood cells, and it has a high risk for transforming into acute myeloid leukemia (AML) [1]. The pathogenesis of MDS is still unclear and may be related to various factors such as molecular genetics, hematopoietic microenvironment changes, hematopoietic stem/progenitor cell proliferation, and apoptosis disorders, immune deficiency, and tumor suppressor gene methylation [2,3]. Given that the benefits of MDS patients from traditional chemotherapy are still very limited, and most MDS patients are elderly patients, most patients have lost the opportunity for transplantation.…”

Section: Introductionmentioning

confidence: 99%

Synergistic inhibitory effect of Smo inhibitor jervine and its combination with decitabine can target Hedgehog signaling pathway to inhibit myelodysplastic syndrome cell line

et al. 2021

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Objective: Hypomethylating agents (HMAs) have been reported to target the Sonic Hedgehog (Shh) signaling pathway in myelodysplastic syndrome (MDS). However, the synergistic inhibitory effect of Smo inhibitor jervine and its combination with decitabine in MUTZ-1 cell lines remains lacking. Methods: We used a CCK-8 assay to detect the in-vitro proliferation rate of MUTZ-1 cell lines. Besides, the Annexin V-FITC/PI double staining flow cytometry was utilized to detect the apoptosis rate and cell cycle changes. The expression levels of mRNA were quantified by using qRT-PCR, and the western blot was employed to detect the expression of proteins. Results: We found that the single-agent jervine or decitabine can significantly inhibit the proliferation rate of MUTZ-1 cell lines, and this inhibitory effect is time-dependent and concentration-dependent. The combined intervention of the jervine and decitabine can more significantly inhibit cell proliferation, induce cell apoptosis, and block the G1 phase of the cell cycle. The combined intervention of the two drugs significantly reduced Smo and G1i-1 mRNA expression in MUTZ-1 cells. Furthermore, after combining both of the drug treatments, the proteins levels of Smo, G1i-1, PI3K, p-AKT, Bcl2, and Cyclin Dl were significantly downregulated, and Caspase-3 is upregulated, indicating that jervine with its combination of decitabine might be effective for controlling the proliferation, apoptosis, and cell cycle. Conclusion:The Smo inhibitor jervine and its combination with decitabine have a synergistic effect on the proliferation, cell cycle, and apoptosis of MUTZ-1 cells, and its mechanism may be achieved by interfering with the Shh signaling pathway.

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ILC1s control leukemia stem cell fate and limit development of AML

et al. 2022

Nat Immunol

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Leukemia Stem Cells in the Pathogenesis, Progression, and Treatment of Acute Myeloid Leukemia

Cited by 3 publications

References 256 publications

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Synergistic inhibitory effect of Smo inhibitor jervine and its combination with decitabine can target Hedgehog signaling pathway to inhibit myelodysplastic syndrome cell line

ILC1s control leukemia stem cell fate and limit development of AML

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