Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors

Nardi, Valentina; Raz, Tal; Cao, Xinyu; Wu, Catherine J.; Stone, Richard; Cortes, Jorge; Deininger, Michael W.; Church, George M.; Zhu, Jun; Daley, George Q.

doi:10.1038/sj.onc.1210698

Cited by 20 publications

(11 citation statements)

References 19 publications

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“…1). Normal range of murine WBC counts can range from 2,000 to 10,000 cells/µL (28). In the first 24 h after injury, the total WBC count was elevated 2-fold in the blood of mice exposed to ethanol before burn and infection when compared with the other treatment groups ( P < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Prolonged Chemokine Expression and Excessive Neutrophil Infiltration in the Lungs of Burn-Injured Mice Exposed to Ethanol and Pulmonary Infection

Murdoch¹,

Karavitis²,

Deburghgraeve³

et al. 2011

Shock

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Pulmonary infections are a major cause of mortality in the critically ill burn patient. Alcohol consumption before burn increases the risk of pulmonary infection. Previously, we have shown an elevated mortality and lung pathology in mice given ethanol before burn and intratracheal infection relative to controls. Here we examine the cellular composition at 24 and 48 h in the circulation and the alveoli of infected mice given alcohol and burn. At 24 h after injury, blood neutrophils obtained from mice exposed to ethanol before burn and infection were 2-fold above those of the experimental controls (P < 0.05). By 48 h, the number of circulating neutrophils decreased and was comparable to levels found in untreated animals. Moreover, at 24 h, bronchoalveolar lavage cells obtained from all treatment groups had similar frequencies and contained 80% neutrophils regardless of treatment. In contrast, the following day, neutrophils were elevated 2-fold only in the alveoli of infected burn animals and 5-fold when ethanol preceded the injury (P < 0.05). These data were confirmed by immunofluorescence microscopy using a neutrophil-specific marker (P < 0.05). Levels of neutrophil chemoattractants, KC and macrophage inflammatory protein 2, and the cytokine, IL-1β, were 2-fold greater in the lungs of infected mice given burn, regardless of ethanol exposure, relative to infected sham injured animals (P < 0.05). Like the number of neutrophils, by the second day after injury, KC and macrophage inflammatory protein 2 remained 5-fold higher in the animals given ethanol, burn, and infection, when compared with other groups (P < 0.05). A similar pattern was seen for pulmonary levels of IL-1β (P < 0.05). Additionally, a reduction in neutrophil apoptosis was observed at the 24-h time point in infected mice exposed to ethanol and burn (P < 0.05). Targeting proinflammatory mediators in mice exposed to ethanol before burn and infection may help alleviate prolonged neutrophil accumulation in the lungs.

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Section: Resultsmentioning

confidence: 99%

Prolonged Chemokine Expression and Excessive Neutrophil Infiltration in the Lungs of Burn-Injured Mice Exposed to Ethanol and Pulmonary Infection

Murdoch¹,

Karavitis²,

Deburghgraeve³

et al. 2011

Shock

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“…Mutations in BCR-ABL were detected by polony assay, described previously (30), or by routine molecular diagnostics at the Brigham and Women’s Hospital, Boston. In the latter process, total RNA was isolated from unfractionated peripheral blood or bone marrow cells, and reverse-transcribed with the ABL primer downstream of the kinase domain and PCR-amplified with primers across the BCR-ABL junction.…”

Section: Methodsmentioning

confidence: 99%

Mutated BCR-ABL Generates Immunogenic T-cell Epitopes in CML Patients

Cai

Keskin

DeLuca

et al. 2012

Clinical Cancer Research

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Purpose: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance.Experimental Design: We assessed whether leukemia neoantigens could be generated from drugresistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML).Results: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC 50 < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC 50 ¼ 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8þ T cells were detected in two imatinib-resistant HLA-A3þ CML patients concurrent with an effective anti-CML response to further therapy.Conclusions: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens.

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“…on May 10, 2018. by guest www.bloodjournal.org From PCR-restriction fragment length polymorphism, 57 polymerase colony assay, 58 allele-specific PCR, 59 and a nanofluidic platform. 60 Whether highly sensitive detection of SGI clinically relevant mutations before SGI therapy will always correlate with their clonal expansion and resistance is unknown.…”

mentioning

confidence: 99%

Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?

Branford

Melo

Hughes

2009

Blood

170

131

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Preclinical studies of BCR-ABL mutation sensitivity to nilotinib or dasatinib suggested that the majority would be sensitive. Correspondingly, the initial clinical trials demonstrated similar response rates for CML patients after imatinib failure, irrespective of the mutation status. However, on closer examination, clinical evidence now indicates that some mutations are less sensitive to nilotinib (Y253H, E255K/V, and F359V/C) or dasatinib (F317L and V299L). T315I is insensitive to both. Novel mutations (F317I/V/C and T315A) are less sensitive/ insensitive to dasatinib. We refer to these collectively as second-generation inhibitor (SGI) clinically relevant mutations. By in vitro analysis, other mutations confer a degree of insensitivity; however, clinical evidence is currently insufficient to define them as SGI clinically relevant. Here we examine the mutations that are clearly SGI clinically relevant, those with minimal impact on response, and those for which more data are needed. In our series of patients with mutations at imatinib cessation and/or at nilotinib or dasatinib commencement, 43% had SGI clinically relevant mutations, including 14% with T315I. The frequency of SGI clinically relevant mutations was dependent on the disease phase at imatinib failure. The clinical data suggest that a mutation will often be detectable after imatinib failure for which there is compelling clinical evidence that one SGI should be preferred. (Blood. 2009; 114:5426-5435)

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Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors

Cited by 20 publications

References 19 publications

Prolonged Chemokine Expression and Excessive Neutrophil Infiltration in the Lungs of Burn-Injured Mice Exposed to Ethanol and Pulmonary Infection

Prolonged Chemokine Expression and Excessive Neutrophil Infiltration in the Lungs of Burn-Injured Mice Exposed to Ethanol and Pulmonary Infection

Mutated BCR-ABL Generates Immunogenic T-cell Epitopes in CML Patients

Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?

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