Chronic myeloid leukemia stem cells: targeting therapeutic implications

Mojtahedi, Hanieh; Yazdanpanah, Niloufar; Rezaei, Nima

doi:10.1186/s13287-021-02659-1

Cited by 42 publications

(31 citation statements)

References 273 publications

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“…Hematopoietic stem cells (HSPCs) are relevant for CML pathogenesis and also for intrinsic or acquired therapy resistance, relapse, and disease progression [ 43 , 44 ]. In order to obtain a deeper mechanistic insight into the functional contribution of SOS1 and/or SOS2 to the process of CML development, here, we isolated the compartment of hematopoietic stem cells (HSPCs) from p210 BCR/ABL transgenic animals of the four relevant SOS genotypes (WT, SOS1-KO, SOS2-KO, and SOS1/2-DKO) and compared their functionality using in vitro colony-formation assays under different experimental conditions, including a TAM treatment for SOS1 ablation and/or imatinib treatments ( Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Gómez

García-Navas

Baltanás

et al. 2022

Cancers

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We showed previously that the ABL-mediated phosphorylation of SOS1 promotes RAC activation and contributes to BCR-ABL leukemogenesis, suggesting the relevant role of SOS1 in the pathogenesis of CML. To try and obtain direct experimental evidence of the specific mechanistic implication of SOS1 in CML development, here, we combined a murine model of CML driven by a p210BCR/ABL transgene with our tamoxifen-inducible SOS1/2-KO system in order to investigate the phenotypic impact of the direct genetic ablation of SOS1 or SOS2 on the pathogenesis of CML. Our observations showed that, in contrast to control animals expressing normal levels of SOS1 and SOS2 or to single SOS2-KO mice, p210BCR/ABL transgenic mice devoid of SOS1 presented significantly extended survival curves and also displayed an almost complete disappearance of the typical hematological alterations and splenomegaly constituting the hallmarks of CML. SOS1 ablation also resulted in a specific reduction in the proliferation and the total number of colony-forming units arising from the population of bone marrow stem/progenitor cells from p210BCR/ABL transgenic mice. The specific blockade of CML development caused by SOS1 ablation in p210BCR/ABL mice indicates that SOS1 is critically required for CML pathogenesis and supports the consideration of this cellular GEF as a novel, alternative bona fide therapeutic target for CML treatment in the clinic.

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Section: Resultsmentioning

confidence: 99%

Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Gómez

García-Navas

Baltanás

et al. 2022

Cancers

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“…This could be due to mechanisms intrinsic to the leukaemic cells that alternatively activate or create de novo parallel bypass survival pathways [ 55 ]. Additionally, because TKIs target only differentiated and cycling cells [ 56 ], certain leukaemic cells could also “escape” the apoptosis induced by TKIs and become dormant [ 56 ]. In this section, we describe the principal BCR::ABL1-independent mechanisms of resistance, including the alternative activation of major BCR::ABL1-driven pathways and other pathways that support alternative survival mechanisms.…”

Section: Bcr::abl1-independent Mechanisms Of Resistance/persistencementioning

confidence: 99%

Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia

Poudel

Tolland

Hughes

et al. 2022

Cancers

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Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1. These patients may require novel therapeutic strategies that target both BCR::ABL1-dependent and BCR::ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR::ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients.

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“…interleukin (IL) 3, granulocyte colony-stimulating factor (G-CSF)]. Other key regulators influencing the apoptosis, self-renewal, cell fate and senescence process of CML SCs include abnormal transforming growth factor-β (TGF-β)/Forkhead box O (FOXO) interaction and Musashi 2 (Msi2)/Numb of NOTCH signaling [97][98][99][100][101][102][103][104][105].…”

Section: CML Tki Treatment and Immune System Functionmentioning

confidence: 99%

Chronic myeloid leukemia: where do we stand, where can we go?

Lewandowski

2022

Acta Haematol Pol.

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The introduction of BCR-ABL tyrosine kinase inhibitors to the treatment of chronic myeloid leukemia (CML) has significantly changed the long term therapy results.After an initial 12 months of therapy with tyrosine kinase inhibitor (TKI), a 3-log reduction of the BCR-ABL copies number on an international scale is possible in 22-46% of patients, depending on the TKI used. In TKI-responsive patients, long-term TKI treatment results are even better, with the BCR-ABL transcript level decreasing over time, even to the point of becoming undetectable. Therefore, an operational cure can be diagnosed in CML patients with an optimal response to 1 st -line TKI treatment, a therapy duration of longer than 5-8 years, and BCR-ABL transcript level below MR4.0-MR4.5 for a period of more than two years. The latter has been the basis of multiple concepts of permanent or periodic discontinuation of TKI treatment [treatment-free remission (TFR)]. Initial TKI discontinuation clinical trials resulted in satisfactory results, with a disease recurrence rate of c.40-60% after 2-3 years. The mechanism of disease recurrence was then studied, with detailed characterization of the CML stem cells (CML SCs) immunophenotype and the mechanisms of survival and self-renewal under TKI selective pressure. A better understanding of the biology of CML allowed the formulation of new therapy concepts of CML SCs eradication, and new criteria for successful TFR qualification.

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Chronic myeloid leukemia stem cells: targeting therapeutic implications

Cited by 42 publications

References 273 publications

Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia

Chronic myeloid leukemia: where do we stand, where can we go?

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