Hematopoietic Stem Cells in Chronic Myeloid Leukemia

Chávez‐González, Antonieta; Avilés-Vázquez, Sócrates; DafneMoreno-Lorenzana,; Mayani, Héctor

doi:10.5772/54651

Cited by 7 publications

(7 citation statements)

References 123 publications

(119 reference statements)

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“…PI3K is activated by forming multimeric complexes with BCR–ABL, Cbl, and adapter molecules such as Crk and Crkl. This leads to activation of another substrate of the cell signaling cascade such as serine–threonine kinase Akt 32…”

Section: Role Of Bcr–abl Kinase In Deregulation Of Crucial Cell Signamentioning

confidence: 99%

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<p>Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities</p>

Flis¹,

Chojnacki²

2019

DDDT

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR–ABL gene fusion. Instead of progress in the understanding of the molecular etiology of CML and the development of novel therapeutic strategies, clinicians still face many challenges in the effective treatment of patients. In this review, we discuss the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development. We also briefly refer to several aspects regarding the current knowledge on the molecular basis of CML and new potential therapeutic targets.

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Section: Role Of Bcr–abl Kinase In Deregulation Of Crucial Cell Signamentioning

confidence: 99%

“…This leads to activation of another substrate of the cell signaling cascade such as serine–threonine kinase Akt. 32 …”

Section: Role Of Bcr–abl Kinase In Deregulation Of Crucial Cell Signamentioning

confidence: 99%

<p>Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities</p>

Flis¹,

Chojnacki²

2019

DDDT

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“…However, one-third of the patients may develop resistance or intolerance to imatinib. These patients can be treated with second generation TKIs, i.e., nilotinib, dasatinib or bosutinib [138, 153]. Nilotinib is an aminopyrimidine that has been engineered to increase its binding to the ATP pocket of BCR-ABL.…”

Section: Targeting Leukemia Stem Cellsmentioning

confidence: 99%

“…Dependent mechanisms involve mutations in the ATP binding domain of BCR-ABL and/or amplification of its encoding fusion gene. Independent mechanisms include reduced expression of the cation transporter hOCT1, which is involved in the influx of imatinib into the cell, increased expression of efflux pumps such as P-glycoprotein (P-gp), sequestration of imatinib by the serum alpha-1-acid glycoprotein (AGP) in plasma, activation of BCR-ABL independent signaling pathways (Src, STAT, Wnt/beta catenin, among others) and LSC-quiescence [153]. …”

Section: Targeting Leukemia Stem Cellsmentioning

confidence: 99%

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

et al. 2016

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Background Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are characterized by high self-renewal and multi-lineage differentiation capacities. CSCs are thought to play indispensable roles in the initiation, progression and metastasis of many types of cancer. Leukemias are thought to be initiated and maintained by a specific sub-type of CSC, the leukemia stem cell (LSC). An important feature of LSCs is their resistance to standard therapy, which may lead to relapse. Increasing efforts are aimed at developing novel therapeutic strategies that selectively target LSCs, while sparing their normal counterparts and, thus, minimizing adverse treatment-associated side-effects. These LSC targeting therapies aim to eradicate LSCs through affecting mechanisms that control their survival, self-renewal, differentiation, proliferation and cell cycle progression. Some LSC targeting therapies have already been proven successful in pre-clinical studies and they are now being tested in clinical studies, mainly in combination with conventional treatment regimens. Conclusions A growing body of evidence indicates that the selective targeting of LSCs represents a promising approach to improve disease outcome. Beyond doubt, the CSC hypothesis has added a new dimension to the area of anticancer research, thereby paving the way for shaping a new trend in cancer therapy.

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“…CML cells express the Philadelphia chromosome (Ph), the product of the balanced translocation t(9;22)(q34;q11) of the long arms of chromosomes 9 and 22,2 giving rise to the oncoprotein p210 Bcr‐Abl 3, 4. Bcr‐Abl is a tyrosine kinase with constitutive activity that drives downstream activation of various signalling pathways that mimic growth factor stimulation, giving cells the ability to evade apoptosis, increase proliferation, differentiation and alter cell adhesion.…”

Section: Introductionmentioning

confidence: 99%

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

Flores‐Lopez

Moreno‐Lorenzana

Ayala-Sánchez

et al. 2018

J Cellular Molecular Medi

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Tyrosine kinase inhibitors (TKI) have become a first‐line treatment for chronic myeloid leuakemia (CML). TKIs efficiently target bulk CML cells; however, they are unable to eliminate the leukaemic stem cell (LSC) population that causes resistance and relapse in CML patients. In this study, we assessed the effects of parthenolide (PTL) and dimethyl amino parthenolide (DMAPT), two potent inhibitors of LSCs in acute myeloid leukaemia (AML), on CML bulk and CML primitive (CD34+lin−) cells. We found that both agents induced cell death in CML, while having little effect on the equivalent normal hematopoietic cells. PTL and DMAPT caused an increase in reactive oxygen species (ROS) levels and inhibited NF‐κB activation. PTL and DMAPT inhibited cell proliferation and induced cell cycle arrest in G0 and G2 phases. Furthermore, we found cell cycle inhibition to correlate with down‐regulation of cyclin D1 and cyclin A. In summary, our study shows that PTL and DMAPT have a strong inhibitory effect on CML cells. Given that cell cycle arrest was not dependent on ROS induction, we speculate that this effect could be a direct consequence of NF‐κB inhibition and if this mechanism was to be evaded, PTL and DMAPT induced cell death would be potentiated.

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Hematopoietic Stem Cells in Chronic Myeloid Leukemia

Cited by 7 publications

References 123 publications

<p>Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities</p>

<p>Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities</p>

Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

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