Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma

Lantermans, Hildo; Minderman, Marthe; Kuil, Annemieke; Kersten, M. J.; Pals, Steven T.; Spaargaren, Marcel

doi:10.1038/s41375-020-0934-6

Cited by 18 publications

(25 citation statements)

References 15 publications

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“…Previous studies have shown that HCK exerts a carcinogenic effect by regulating the ERK gene in BCR/ABL-positive ALL and B-ALL [13,15]. ERK1/2 pathway have been identi ed in human myeloid leukaemia, and abnormal activation enhances the proliferation and survival of myeloid cells [43]. In our study, we considered that HCK might regulate CDK6 expression through the ERK1/2-c-Myc axis.…”

Section: Discussionmentioning

confidence: 96%

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

Wang

Long

et al. 2021

Preprint

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Background: Leukaemia stem cells (LSCs) are responsible for the initiation, maintenance, and recurrence of acute myeloid leukaemia (AML), an aggressive haematological malignancy associated with drug resistance and relapse. Identifying therapeutic LSC targets is critical to curing AML.Methods: Bioinformatics databases were used to identify therapeutic LSC targets. The conditional knockout mice were used to analyse the role of HCK in leukaemogenesis or normal haematopoiesis. Colony-forming assays, cell counting, and flow cytometry were used to detect the viability and function of leukaemia cells. RT-PCR, western blotting, and RNA sequencing were used to detect mRNA and protein expression.Result: HCK is expressed at higher levels in LSCs than in haematopoietic stem cells (HSCs), and high HCK levels are correlated with reduced survival time in AML patients. Knockdown of HCK leads to cell cycle arrest, which results in a dramatic decrease in the proliferation and colony formation in human AML cell lines. Moreover, HCK is required for leukemogenesis and leukaemia maintenance in vivo and in vitro. HCK is necessary for the self-renewal of LSCs during serial transplantation and limiting dilution assay. The phenotypes resulting from HCK deficiency can be rescued by CDK6 overexpression in the human cell line. RNA sequencing and gene expression have demonstrated that HCK may sustain cell cycle entry and maintain the self-renewal ability of LSCs through activating the ERK1/2-c-Myc-CDK6 signalling axis. In contrast, HCK deletion does not affect normal haematopoiesis or haematopoietic reconstruction in mice.Conclusion: HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML and may be an ideal therapeutic target for eradicating LSCs without influencing normal haematopoiesis.

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Section: Discussionmentioning

confidence: 96%

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

Wang

Long

et al. 2021

Preprint

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“…Importantly, SFK members exhibit complementary and often functionally redundant roles in several signal transduction pathways. For example, FYN and LCK cooperate in T-cell receptor-mediated activation, and HCK and FGR cooperate to regulate macrophage phagocytosis [13,34,46]. This functional overlap between SFK members has been shown to play an essential role in maintaining relatively normal immune responses, which may be the cause that the effect of HCK on the self-renewal ability of LSCs is not fatal.…”

Section: Discussionmentioning

confidence: 99%

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

Wang

Tian

et al. 2021

J Exp Clin Cancer Res

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Background: Leukaemia stem cells (LSCs) are responsible for the initiation, maintenance, and recurrence of acute myeloid leukaemia (AML), an aggressive haematological malignancy associated with drug resistance and relapse. Identifying therapeutic LSC targets is critical to curing AML. Methods Bioinformatics databases were used to identify therapeutic LSC targets. The conditional knockout mice were used to analyse the role of HCK in leukaemogenesis or normal haematopoiesis. Colony-forming assays, cell counting, and flow cytometry were used to detect the viability and function of leukaemia cells. RT-PCR, western blotting, and RNA sequencing were used to detect mRNA and protein expression. Result HCK is expressed at higher levels in LSCs than in haematopoietic stem cells (HSCs), and high HCK levels are correlated with reduced survival time in AML patients. Knockdown of HCK leads to cell cycle arrest, which results in a dramatic decrease in the proliferation and colony formation in human AML cell lines. Moreover, HCK is required for leukemogenesis and leukaemia maintenance in vivo and in vitro. HCK is necessary for the self-renewal of LSCs during serial transplantation and limiting dilution assay. The phenotypes resulting from HCK deficiency can be rescued by CDK6 overexpression in the human cell line. RNA sequencing and gene expression have demonstrated that HCK may sustain cell cycle entry and maintain the self-renewal ability of LSCs through activating the ERK1/2-c-Myc-CDK6 signalling axis. In contrast, HCK deletion does not affect normal haematopoiesis or haematopoietic reconstruction in mice. Conclusions HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML and may be an ideal therapeutic target for eradicating LSCs without influencing normal haematopoiesis.

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“…The mutated form of MYD88 has been shown to trigger transcription and activation of HCK in Waldenström macroglobulinemia 57 , a disease that shares genetic and biological features with ABC DLBCL. HCK has been discussed as a possible therapeutic target for small molecule inhibitors in multiple cancers 58 and high expression of HCK has been associated with poor prognosis in mantle cell lymphoma 59 . Overexpression of HCK in other cancers can contribute to epithelial mesenchymal transition (EMT), hypoxia and TGFβ signaling 60 .…”

Section: Discussionmentioning

confidence: 99%

Non-coding NFKBIZ 3′ UTR mutations promote cell growth and resistance to targeted therapeutics in diffuse large B-cell lymphoma

Arthur

Gao

Healy

et al. 2021

Preprint

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Amplifications and non-coding 3′ UTR mutations affecting NFKBIZ have been identified as recurrent genetic events in diffuse large B-cell lymphoma (DLBCL). We confirm the prevalence and pattern of NFKBIZ 3′ UTR mutations in independent cohorts and determine they are enriched in the ABC subtype as well as the recently described novel C1/BN2/NOTCH2 classes of DLBCL. Presently, the effects of and mechanism by which non-coding mutations can act as cancer drivers has been relatively unexplored. Here, we provide a functional characterization of these non-coding NFKBIZ 3′ UTR mutations. We demonstrate that the resulting elevated expression of IκB-ζ confers growth advantage in DLBCL cell lines and primary germinal center B-cells as well as nominate novel IκB-ζ target genes with potential therapeutic implications. The responses to targeted treatments in DLBCL, particularly those targeting the NF-κB axis, led us to investigate and confirm that NFKBIZ 3′ UTR mutations affect response to therapeutics and suggest it may be a useful predictive biomarker.

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Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma

Cited by 18 publications

References 15 publications

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML

Non-coding NFKBIZ 3′ UTR mutations promote cell growth and resistance to targeted therapeutics in diffuse large B-cell lymphoma

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