Similar patterns of chromosome abnormalities in CML occur in addition to the Philadelphia chromosome with or without tyrosine kinase inhibitor treatment

Haferlach, Claudia; Bacher, Ulrike; Schnittger, Susanne; Weiss, Tamara; Kern, Wolfgang; Haferlach, Torsten

doi:10.1038/leu.2009.222

Cited by 27 publications

(19 citation statements)

References 9 publications

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“…3 Therefore, persistent activation of the Rac2-MRC-cIII-ROS oxidative DNA damage pathway may allow a relatively unabated accumulation of genetic aberrations independently of whether CML-CP patients appear to be responding to imatinib. 50 In conclusion, we postulate that the genomic instability responsible for the generation of TKI-resistant and/or CML-BP clones may occur in LSCs and/or LPCs and depends on the Rac2-MRC-cIII axis as a major stimulator of ROS-induced oxidative DNA damage in these cells (supplemental Figure 8). The application of mitochondrial ROS scavengers in patients treated with imatinib may prevent the emergence of mutated clones.…”

Section: Discussionmentioning

confidence: 99%

Rac2-MRC-cIII–generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Nieborowska‐Skorska

Kopiński

Ray

et al. 2012

Blood

157

144

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Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII–generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor–resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)–positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.

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Section: Discussionmentioning

confidence: 99%

Rac2-MRC-cIII–generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Nieborowska‐Skorska

Kopiński

Ray

et al. 2012

Blood

157

144

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“…This observation suggests that genomic instability is an early event in CML. Patients from the pre-imatinib and imatinib era display similar types of genetic aberrations (125).…”

Section: Consequences Of Genomic Instability In CMLmentioning

confidence: 99%

Chronic myeloid leukemia: mechanisms of blastic transformation

Perrotti¹,

Goldman²,

Skórski³

2010

J. Clin. Invest.

361

367

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“…113 The pattern of chromosome abnormalities is not altered by TKI treatment. 114 The prognostic impact of ACA may depend on the type of ACA. 112 Some ACA types (major route, complex karyotypes) appear to imply poorer prognosis than others that may only indicate genetic instability.…”

Section: Can Bc Be Prevented? Is Early Prediction Possible?mentioning

confidence: 99%