Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Ranganathan, Parvathi; Yu, Xinmin; Na, Caroline; Santhanam, Ramasamy; Shacham, Sharon; Kauffman, Michael; Walker, Alison; Klisovic, Rebecca B.; Blum, William; Caligiuri, Michael A.; Croce, Carlo M.; Marcucci, Guido; Garzon, Ramiro

doi:10.1182/blood-2012-04-423160

Cited by 187 publications

(257 citation statements)

References 49 publications

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“…[43][44][45][46] Several studies have provided evidence that a new leucine-rich NES created by the NPMc þ mutation promotes CRM1-dependent nuclear export of NPMc þ , thus resulting in accumulation of NPMc þ in the cytoplasm. [5][6][7]47,48 In the current study, we demonstrate that the redox-sensitive C288 generated by the NPMc þ mutation has an important role in regulating the cytoplasmic accumulation of NPMc þ . Mutation of C288 to alanine enables NPMc þ to remain in the nucleolus, suggesting that this cysteine residue may be sufficient to cause cytoplasmic localization independent of the loss of W288 and the acquisition of additional leucine-rich nuclear export motifs resulting from the C-terminal extension.…”

Section: Discussionmentioning

confidence: 83%

“…Mutation of C288 to alanine enables NPMc þ to remain in the nucleolus, suggesting that this cysteine residue may be sufficient to cause cytoplasmic localization independent of the loss of W288 and the acquisition of additional leucine-rich nuclear export motifs resulting from the C-terminal extension. [5][6][7] The observation, that C21A and C104A mutations disrupt the oligomerization of NPMc þ but do not alter its cytoplasmic localization, suggests that these two cysteines do not participate in the redox-mediated changes in localization and that localization is independent of the oligomerization status of NPMc þ . Our results are consistent with the recent finding that fusion proteins containing the most common NPM COOH-terminal LxxxVxxVxL export signals that are present in the majority of NPMc þ mutations are not exported into the cytoplasm.…”

Section: Discussionmentioning

confidence: 93%

“…5,6 This conclusion is based on the introduction of a variety of site-directed mutants containing NES variants into cell lines, and is supported by the observation that the cytoplasmic accumulation of NPMc þ mutants is blocked by specific inhibitors of the nuclear export protein, Crm1/exportin-1. [5][6][7] In addition, reinsertion of tryptophan into the mutated protein at position 288 disrupts the NES site and restores nucleolar localization of the protein. 5 Bortezomib, a specific inhibitor of the 20S proteasome, has displayed clinical efficacy in a number of hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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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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“…Mechanistically, overexpression of XPO1 enhances export of nuclear tumor suppressor proteins such as p53, BRCA1, allophycocyanin, and NMP1, resulting in drug resistance. 33 Overexpression of XPO1 has also been associated with drug resistance and poor outcome in many solid tumors such as glioblastoma, cervical and ovarian cancer, [35][36][37] and various hematologic malignancies, including myeloma, 38 chronic lymphocytic leukemia, 26 T-cell acute lymphoblastic leukemia, acute myeloid leukemia, [39][40][41] and BCR-ABL1-driven blastic transformation. 19,42 In the shRNA library screen, shRAN-infected cells were depleted by fourfold in K562 R compared with K562 S cells (supplemental Table 4) following 9 days in culture.…”

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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“…As an isolated molecular abnormality, NPM1 is associated with a highly favorable prognosis, with CR rates between 70-80% and PFS and OS similar to those in CBF mutated AML [75,76]; however, concurrent FLT3-ITD mutations are present in onethird of cases and counteract the positive prognostic impact of the NPM1 mutation [3,76]. Selective inhibitors of nuclear export (SINEs), which bind to and inhibit the activity of the exportin-1 (XPO1) receptor, have shown promising results in preclinical and clinical studies of AML patients [77]. This represents a potentially novel treatment strategy in patients whose leukemia is characterized by mutations that alter normal nuclear export.…”

Section: Npm1mentioning

confidence: 99%

The Impact of Molecular Genetic in Acute Myeloid Leukemias

Patriarca¹,

Salutari²,

S³

2015

J Blood Disord Transfus

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The discovery and application of advanced molecular techniques, such as gene and microRNA expression profiling, whole genome and exome sequencing and methylation assays, allowed for the identification of recurrent molecular abnormalities in acute myeloid leukemia (AML) that have revolutionized our understanding of the genetic landscape of the disease. Moreover, these modalities have emerged as valuable tools that permit a more comprehensive and detailed molecular characterization of AML, helping in the prediction of prognosis, particularly within the context of cytogenetically normal AML (CN-AML). This review will discuss the major techniques and platforms that have been used to identify novel recurrent gene mutations in AML and briefly describe how these discoveries have impacted on outcome prediction.

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Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia

Cited by 187 publications

References 49 publications

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

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

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

The Impact of Molecular Genetic in Acute Myeloid Leukemias

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