European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests

Advances in the treatment of chronic myeloid leukemia

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance

Phospho-CRKL monitoring for the assessment of BCR-ABL activity in imatinib-resistant chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia patients treated with nilotinib

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Does the Constitution Provide More Ballot Access Protection for Presidential Elections Than for U.S. House Elections?

Both the U.S. Constitution and The Federalist Papers suggest that voters ought to have more freedom to vote for the candidate of their choice for the U.S. House of Representatives than they do for the President or the U.S. Senate. Yet, strangely, for the last thirty-three years, the U.S. Supreme Court and lower courts have ruled that the Constitution gives voters more freedom to vote for the candidate of their choice in presidential elections than in congressional elections. Also, state legislatures, which have been writing ballot access laws since 1888, have passed laws that make it easier for minor-party and independent candidates to get on the ballot for President than for the U.S. House. As a result, voters in virtually every state invariably have far more choices on their general election ballots for the President than they do for the House. This Article argues that the right of a voter to vote for someone other than a Democrat or a Republican for the House is just as important as a voter’s right to do so for President, and that courts should grant more ballot access protection to minor-party and independent candidates for the House

Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms

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Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib

The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of ‘ATPase activity', ‘cell adhesion' or ‘tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance