Myeloproliferative neoplasms (MPNs) are myeloid malignancies characterized by stem cell-derived clonal myeloproliferation. There are seven designated conditions under the category of MPNs including chronic myelogenous leukemia (CML) and polycythemia vera (PV). CML is characterized by the presence of the Philadelphia chromosome (Ph), a translocation involving chromosomes 9 and 22 that results in...

The primary treatment modality for cancer involves surgical resection of the tumor(s) followed by radiation and chemotherapy. In some cases where the cancer, particularly pancreatic cancer, has advanced to a stage that precludes surgery, chemotherapy remains the standard of care. There are two types of drugs that are normally used in chemotherapy, both types usually guided by rational or struct...

In the article by Lee et al. (1), an alternative splicing of BCR-ABL is proposed as a mechanism for imatinib resistance in chronic myeloid leukemia (CML) patients. This splicing (2), which inserts 35 bp between exons 8 and 9 of ABL (35INS), results in a truncated BCRABL protein that the authors compare dynamically with the native protein. We found their work very relevant, especially the findin...

Acquired pointmutationswithin the BCR-ABL kinase domain represent a commonmechanismof resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABL mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds...

Fludarabine (Flu) and 2-chlorodeoxyadenosine (2-CdA) are purine analogs with antineoplastic activity in lymphoproliferative malignancies. We recently showed in vitro the effective role of Flu and 2-CdA in the activation of apoptosis. We observed a dramatic induction of apoptosis in vitro by Flu (Figure 1) and 2-CdA on fresh CML cells, with or without the association of IFN-a. The mechanism behi...

Background: Despite durable responses to imatinib in chronic myeloid leukaemia (CML), mutations in Bcr-Abl kinase domain (KD) are known to induce imatinib resistance and cause poor clinical outcome. Methods: We characterized Bcr-Abl KD mutations in 20 Egyptian CML patients with imatinib resistance (n = 12) or responsive (n = 8) using allele specific oligonucleotide polymerase chain reaction (PC...

Several signaling cascades are engaged by expression of the p210 bcr-abl tyrosine kinase, and evidence suggests that these signals drive leukemogenesis. In this report, signaling pathways were examined and compared between cells derived from leukemic patients and cells expressing a bcr-abl construct (MBA). The effects of acute inhibition of bcr-abl with STI-571 on these signals and the survival...

In chronic phase chronic myeloid leukemia (CML), the BCR-ABL kinase inhibitor imatinib leads to complete cytogenetic responses in the majority of cases. Resistance towards imatinib is associated with BCR-ABL kinase domain mutations, leading to structural changes that prevent imatinib from binding. In cases of failure towards imatinib treatment, second generation BCR-ABL kinase inhibitors such a...

The majority of cancer therapies target macromolecules important for general cell survival, such as DNA, topoisomerase, and tubulin (e.g. , cisplatin, doxorubicin, and paclitaxel, respectively). While these agents are effective at killing many types of cancer cells, they also affect rapidly dividing normal cells, such as the intestinal lining and bone marrow, resulting in dose limiting toxiciti...

Interactions between the kinase inhibitor STI571 and pharmacological antagonists of the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) cascade have been examined in human myeloid leukemia cells (K562 and LAMA 84) that express the Bcr-Abl kinase. Exposure of K562 cells to concentrations of STI571 that minimally induced apoptos...