Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Heaney, Nicholas; Pellicano, Francesca; Zhang, Bin; Crawford, Lisa; Chu, Su; Kazmi, Syed Mohammad Ali; Allan, Elaine; Jørgensen, Heather G.; Irvine, Alexandra; Bhatia, Ravi; Holyoake, Tessa L.

doi:10.1182/blood-2008-06-164582

Cited by 52 publications

(52 citation statements)

References 49 publications

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“…Very recently, Heaney and co-workers have also shown that Btz induces apoptosis of primary CD34 þ cells and also the more primitive CD34 þ 38-cells from CML patients. These authors show that Btz reduces (1) the capacity of these cells to form colonies in long-term cultures and (2) the engraftment potential of these human CD34 þ CML cells (Heaney et al, 2010). This indicates that Btz can target CML stem cells that are resistant to IM treatment.…”

Section: Discussionmentioning

confidence: 89%

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

et al. 2010

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Section: Discussionmentioning

confidence: 89%

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

et al. 2010

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“…In particular, 5 of the top 50 genes (PSMA1, UBE1, NEDD8, PSMD3, and PSMD1) are associated with proteasomedependent protein degradation, which has been implicated in TKI resistance of CML stem and progenitor cells. 44 In addition, 3 of the top 50 genes (TXN, RPA3, and MUS81) are associated with DNA damage or repair pathways, adding to the observation of increased homologous recombination repair in samples from imatinib nonresponders, 45 and a report implicating RAD52 as a target to enhance the effects of TKIs on CML cells. 46 Drug resistance remains a significant clinical problem in targeted cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562 R , a CML cell line with BCR-ABL1 kinaseindependent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562 R cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34 1 cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34 1 cells from normal cord blood or from a patient harboring the BCR-ABL1 T315I mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML. (Blood. 2015;125(11):1772-1781

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“…5 Bortezomib, a specific inhibitor of the 20S proteasome, has displayed clinical efficacy in a number of hematologic malignancies. [8][9][10][11][12] In addition to its direct inhibitory effects on the proteasome, 9 bortezomib has been noted to increase the level of intracellular reactive oxygen species (ROS) as an important component of its ability to induce apoptosis, [13][14][15][16][17][18] autophagy [19][20][21] and differentiation. 22 A sustained increase in ROS generation appears, in turn, to enhance the inhibitory effects of bortezomib on proteasomal activity.…”

Section: Introductionmentioning

confidence: 99%

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Huang

Thomas

et al. 2013

Leukemia

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Mutations in exon 12 of the nucleophosmin (NPM1) gene (NPMc þ (NPM1 COOH terminal mutations)) define a distinct subset of acute myelogenous leukemias (AMLs), in which the NPMc þ protein localizes aberrantly to the leukemic cell cytoplasm. We have found that introduction of the most common NPMc þ variant into K562 and 32D cells sensitizes these cells to apoptosis induced by drugs such as bortezomib and arsenic trioxide (ATO) that induce reactive oxygen species (ROS) formation, and that cytotoxicity is prevented in the presence of N-acetyl-L-cysteine (NAC), an ROS scavenger. The substitution of tryptophan 288 (W288) by cysteine occurs in the great majority of NPM1c þ mutations. Mutagenesis of cysteine 288 to alanine re-localizes NPMc þ from the cytoplasm to the nucleolus and attenuates the sensitivity of cells expressing this mutation to bortezomib and ATO. Primary AML cells expressing NPMc þ are also significantly more sensitive than other AML cells to apoptosis induced by both drugs at pharmacologically achievable doses. We conclude that the presence of a cysteine moiety at position 288 results in the cytoplasmic localization of NPM1c þ and the increased sensitivity to bortezomib and ATO. These data suggest that bortezomib and ATO may have increased therapeutic efficacy in NPM1c þ leukemias.

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Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells

Cited by 52 publications

References 49 publications

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

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