Bortezomib suppresses self‐renewal and leukemogenesis of leukemia stem cell by NF‐ĸB‐dependent inhibition of CDK6 in MLL‐rearranged myeloid leukemia

Zhou, Bin; Qin, Yaqian; Zhou, Jingying; Ruan, Jian; Xiong, Fang; Dong, Jinglai; Huang, Xingzhou; Yu, Zhijie; Gao, Shenmeng

doi:10.1111/jcmm.16377

Cited by 7 publications

(14 citation statements)

References 40 publications

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“…The authors demonstrated that bortezomib suppressed the self-renewal ability of LSCs by inhibiting the recruitment of NF-κB to Cyclin dependent kinase 6 (CDK6) promoter and consequently the expression of CDK6. Since bortezomib acts selectively against LSCs with little side effects againts normal HSPC, these studies supports the potential use of bortezomib in AML patients with MLL rearrangements [ 122 ].…”

Section: Nf-κb Core Pathway Inhibitorsmentioning

confidence: 59%

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Francesco

Verzella

Capece

et al. 2022

Cancers

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Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic options are still urgently needed. Constitutive NF-κB activation has been reported in around 40% of AML patients, where it sustains AML cell survival and chemoresistance. Given the central role of NF-κB in AML, targeting the NF-κB pathway represents an attractive strategy to treat AML. This review focuses on current knowledge of NF-κB’s roles in AML pathogenesis and summarizes the main therapeutic approaches used to treat NF-κB-driven AML.

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Section: Nf-κb Core Pathway Inhibitorsmentioning

confidence: 59%

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Francesco

Verzella

Capece

et al. 2022

Cancers

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“…Bortezomib treatment has also been shown to increase the overall survival and reduce the self-renewal capacity of leukemic stem cells in mouse leukemic cells expressing MLL-AF9, a KMT2A fusion protein. The cell cycle regulatory protein kinase CDK6 has been demonstrated to be one of the important targets of bortezomib in myeloid-derived KMT2A-r leukemia 19 . The same study also showed that, mechanistically, the effect of bortezomib was mediated by the reduction in CDK6 expression by preventing the recruitment of NF-κ B to the CDK6 promoter.…”

Section: Discussionmentioning

confidence: 87%

“…The cell cycle regulatory protein kinase CDK6 has been demonstrated to be one of the important targets of bortezomib in myeloid-derived KMT2A-r leukemia. 19 The same study also showed that, mechanistically, the effect of bortezomib was mediated by the reduction in CDK6 expression by preventing the recruitment of NF-κ B to the CDK6 promoter. With respect to other potential mechanisms, quantitative mass spectrometry on KMT2A-r ALL protein samples treated with bortezomib resulted in the upregulation of proteins like ATF4, which is known to be involved in the endoplasmic reticulum (ER) stress-induced cell death.…”

Section: Discussionmentioning

confidence: 90%

“…Additional studies have indicated the potential use of bortezomib for the treatment of both myeloid and lymphoid KMT2A-r infant leukemia. 19,23 Bortezomib treatment has also been shown to increase the overall survival and reduce the selfrenewal capacity of leukemic stem cells in mouse leukemic cells expressing MLL-AF9, a KMT2A fusion protein. The cell cycle regulatory protein kinase CDK6 has been demonstrated to be one of the important targets of bortezomib in myeloid-derived KMT2A-r leukemia.…”

Section: Discussionmentioning

confidence: 99%

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Establishment of a t(11;19), KMT2A Rearranged B-ALL Cell Line for Preclinical Evaluation and Novel Therapeutics Development for Refractory Infant Leukemia

Incoronato

Zhang

Jayanthan³

et al. 2023

Journal of Pediatric Hematology/Oncology

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Leukemia, diagnosed in children less than 12 months of age, is a rare condition with an aggressive disease presentation and poor response to conventional chemotherapeutic agents. In addition, the unique vulnerability of the affected population does not always permit the use of markedly intense regimens with higher doses of cytotoxic agents. However, the unique biology of these leukemic cells also provides opportunities for the identification of effective and potentially well-tolerated targeted therapeutic strategies. In this report, we describe the establishment and characterization of a cell line from the blasts of an infant diagnosed with refractory B-cell acute lymphoblastic leukemia (ALL) carrying the characteristic histone lysine methyltransferase 2A (KMT2A) gene rearrangement. This cell line consists of rapidly proliferating clones of cells with chemosensitivity patterns previously described for KMT2A rearranged leukemia cells, including relative resistance to glucocorticoids and sensitivity to cytarabine. We also show effective targetability with menin inhibitors, indicating the activity of abnormal KMT2A-related pathways and the potential utility of this cell line in comprehensive drug library screens. Overall, our findings report the establishment and in vitro validation of a cell line for research into key aspects of infant leukemia biology and targeted therapeutics development.

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“…Despite the large number of tests involving TKIs, medications and methodologies have also been developing as the case of Bortezomibe. Its function is based on decreasing the expression of CDK6, an important agent in the proliferation of LSCs (120,125,126).…”

Section: Treatment Perspectivesmentioning

confidence: 99%

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Barreto

Pessoa²,

Machado³

et al. 2022

Front. Oncol.

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Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

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Bortezomib suppresses self‐renewal and leukemogenesis of leukemia stem cell by NF‐ĸB‐dependent inhibition of CDK6 in MLL‐rearranged myeloid leukemia

Cited by 7 publications

References 40 publications

NF-κB: A Druggable Target in Acute Myeloid Leukemia

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Establishment of a t(11;19), KMT2A Rearranged B-ALL Cell Line for Preclinical Evaluation and Novel Therapeutics Development for Refractory Infant Leukemia

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

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