The chronic myeloid leukemia stem cell: stemming the tide of persistence

Holyoake, Tessa L.; Vetrie, David

doi:10.1182/blood-2016-09-696013

Cited by 244 publications

(245 citation statements)

References 148 publications

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“…Treatments with imatinib, for example, in chronic myeloic leukemia, as monotherapy can lead to long lasting molecular remission and operational cure [17]. In ABL-activated acute leukemias, however, imatinib is only beneficial when incorporated into combined cytotoxic regimes.…”

Section: Reviewmentioning

confidence: 99%

Precision medicine in pediatric oncology

et al. 2018

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Outcome in treatment of childhood cancers has improved dramatically since the 1970s. This success was largely achieved by the implementation of cooperative clinical research trial groups that standardized and developed treatment of childhood cancer. Nevertheless, outcome in certain types of malignancies is still unfavorable. Intensification of conventional chemotherapy and radiotherapy improved outcome only marginally at the cost of acute and long-term side effects. Hence, it is necessary to develop targeted therapy strategies.Here, we review the developments and perspectives in precision medicine in pediatric oncology with a special focus on targeted drug therapies like kinase inhibitors and inducers of apoptosis, the impact of cancer genome sequencing and immunotherapy.

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Section: Reviewmentioning

confidence: 99%

Precision medicine in pediatric oncology

et al. 2018

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“…As many studies using murine retroviral bone marrow transplantation models or xenograft transplantation models have consistently shown, CML is maintained by a very small number of CML LSCs, as is the case of hierarchicallystructured normal hematopoietic system, sustained by self-renewing HSCs at the apex of developmental hierarchy (1,8,9). Molecular bases of persisting disease after TKI therapy have been extensively investigated, and many studies have attributed them to LSC persistence even under prolonged and apparently efficacious TKI treatment (10).…”

Section: Leukemia Stem Cells (Lscs)mentioning

confidence: 99%

“…CML LSCs, unlike their differentiated progenies, don't depend on BCR-ABL signaling for their survival, in other words, they are free from oncogene addiction (11). Importantly, CML LSCs are very similar to normal HSCs in many aspects, not only indicating the fact that CML LSCs are derived from HSCs, but also suggesting inherent difficulties in selectively eradicating LSCs without sparing HSCs (1,9).…”

Section: Leukemia Stem Cells (Lscs)mentioning

confidence: 99%

“…These studies have illustrated that most key molecules essential for the maintenance of stemness are shared by LSCs and HSCs, including those implicated in transcription, regulation of cell cycle, metabolism, autophagy, signal transduction, and niche-associated factors, while LSCs are more dependent on some of these factors than HSCs, providing potential therapeutic opportunities (1). Among them, a long list of studies have probed into the role of Wnt/β-catenin signaling in normal and malignant hematopoiesis, including the pathogenesis of CML, as depicted in recent reviews (12,13).…”

Section: Wnt/β-catenin Signaling and Its Related Factors In Hscs And mentioning

confidence: 99%

“…Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by clonal expansion and accumulation of differentiated myeloid cells in the blood and the bone marrow (1). CML usually begins with chronic phase, where expanded myeloid cells are almost normal in terms of function.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting chronic myeloid leukemia stem cells: can transcriptional program be a druggable target for cancers?

Masamoto

Kurokawa

2018

Stem Cell Investig.

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from acquisition of constitutively active BCR-ABL protein tyrosine kinase in a hematopoietic stem cell (HSC). Though tyrosine kinase inhibitors (TKIs) have changed a fatal disease into manageable disease, most patients cannot discontinue TKI treatment due to persistence of TKI-resistant leukemia stem cells (LSCs). Much effort has been made to find out factors or pathways specifically operating in LSCs to selectively target LSCs, with some promising results at least in preclinical models. In this article, we briefly review the role of Wnt/ β-catenin signaling and its related factors in CML LSCs, especially focusing on Tcf1/Lef1 transcription factors, major effectors of Wnt/β-catenin pathway, of which transcriptional program have recently been shown to be targetable with prostaglandin E1.

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Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia

et al. 2018

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The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long‐term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr‐Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM‐resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM‐resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF‐κB, MEK‐ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS‐1145 (IκB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM‐resistant cells and reduction in the colony‐forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF‐κB signaling attenuates the survival of IM‐resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients.

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The chronic myeloid leukemia stem cell: stemming the tide of persistence

Cited by 244 publications

References 148 publications

Precision medicine in pediatric oncology

Precision medicine in pediatric oncology

Targeting chronic myeloid leukemia stem cells: can transcriptional program be a druggable target for cancers?

Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia

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