Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells

  title={Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells},
  author={Andrzej Ptasznik and Yuji Nakata and Anna Kalota and Stephen G Emerson and Alan M. Gewirtz},
  journal={Nature Medicine},
We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. [...] Key Result Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80–95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent apoptosis, whereas normal cells remained viable. This increased dependence on Lyn signaling for BCR-ABL1(+) blast survival provides the basis for rational treatment of drug-resistant…Expand
BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia.
Up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1 is described, indicating that Fyn mediates CML cell proliferation and encourages the development of therapies targeting Fyn expression. Expand
Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.
It is shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells and the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of Autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Expand
Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia positive cells including primary CML stem cells
Imatinib mesylate (IM), a potent ATP-competitive inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequencyExpand
Gene therapy for BCR‐ABL+ human CML with dual phosphorylation resistant p27Kip1 and stable RNA interference using an EBV vector
BCR‐ABL‐mediated chronic myelogenous leukemia (CML) CD34+ cell proliferation mostly depends on the nucleo‐cytoplasmic ratio of the cyclin‐dependent kinase inhibitor p27. The ubiquitin‐ligase SCFSkp2Expand
Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase.
Reducing LYN expression (siRNA) or activation (dasatinib) was associated with loss of cell survival and cytogenetic or complete hematologic responses in imatinib-resistant disease and LYN activation was independent of BCR-ABL in cells from imatinIB-resistant patients. Expand
Targeting primary human leukaemia cells with RNA interference: Bcr‐Abl targeting inhibits myeloid progenitor self‐renewal in chronic myeloid leukaemia cells
Through the functional targeting of an oncogene in primary human tumour cells, it is demonstrated that Bcr‐Abl enhances CML progenitor cell amplification, and that RNAi may be suitable for development as a specific anti‐leukaemia treatment. Expand
Combinations of Novel Histone Deacetylase and Bcr-Abl Inhibitors in the Therapy of Imatinib Mesylate-Sensitive and -Refractory Bcr-Abl Expressing Leukemia
Cotreatment with LBH589 and AMN107 is active against cultured or primary IM-resistant CML cells, including those with expression of Bcr-AblT315I. Expand
Persistent LYN signaling in imatinib-resistant, BCR-ABL-independent chronic myelogenous leukemia.
Investigation of a BCR-ABL mutation provides an explanation for onset of imatinib resistance and indicates a clear treatment strategy: second-line therapy with an ABL kinase inhibitor that is active against the particular BCR -ABL variant kinase. Expand
NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.
The results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia. Expand
Kinase inhibition: Life and LYN
  • K. Novak
  • Chemistry, Biology
  • Nature Reviews Cancer
  • 2004
This study is the first to use siRNA to validate therapeutic targets in primary leukaemia cells, and the authors suggest that this approach might also be developed for therapeutic use. Expand


BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.
Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression, and results suggest that acquired STi571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases. Expand
Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia
The results implicate Src family kinases as therapeutic targets in Ph+ B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph+ acute leukemia. Expand
Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3.
Findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis. Expand
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested. Expand
Crosstalk Between BCR/ABL Oncoprotein and CXCR4 Signaling through a Src Family Kinase in Human Leukemia Cells
It is demonstrated, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. Expand
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer. Expand
Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells.
The results show that p210bcr/abl induces the activation of at least two Src family kinases, P53/56lyn and p59hck, in myeloid cells, which extends the range of potential targets of p2l0bCr/abl that might mediate its transforming effects. Expand
The biology of CML blast crisis.
Validation of the critical role of certain secondary changes (ie, loss of p53 or C/EBPalpha function) in murine models of CML blast crisis and in in vitro assays of BCR/ABL transformation of human hematopoietic progenitors might lead to the development of novel therapies based on targeting BCR /ABL and inhibiting or restoring the gene activity gained or lost during disease progression. Expand
The Src-selective Kinase Inhibitor PP1 Also Inhibits Kit and Bcr-Abl Tyrosine Kinases*
PP1 completely abrogated the proliferation of M07e cells in response to SCF and suggest that PP1 or related compounds may be useful in the treatment of malignant diseases associated with dysregulated c-Kit or Abl tyrosine kinase activity. Expand
Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study.
Antisense oligodeoxynucleotide (ODN) drugs might be more effective if their delivery was optimized and they were targeted to short-lived proteins encoded by messenger RNA (mRNA) species with equallyExpand