p38 in chronic myelogenous leukemia: a target and a possible biomarker

The introduction of BCR/ABL tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML) has revolutionized the treatment of this disease. Broadly, these TKIs act by inhibiting the oncogenic activity of BCR/ABL gene in CML cells, which ultimately results in growth arrest and apoptosis of leukemia cells. Imatinib mesylate (IM) was the first novel TKI that was approved for CML treatment. Based on results from the International Randomized Interferon versus STI571 (IRIS) trial [1], patients with CML start oral treatment with IM instead of receiving toxic therapies of past such as interferon-a and bone marrow transplantation. This approach has produced dramatic long-term remissions with good quality of life [1]. Unfortunately, not all patients who are treated with IM achieve longterm remissions. Recent updates from the IRIS study indicate that approximately 20–30% of patients with CML are either intolerant to IM or develop drug resistance. Resistance to IM commonly results from either mutations in BCR-ABL kinase domains or BCR/ABL gene amplification [2]. This understanding has led to development and testing of a plethora of new agents in both preclinical and clinical settings. Among the second generation of TKIs, dasatinib and nilotinib are approved for use in patients with imatinib-resistant and/or -intolerant CML. Dasatinib is recognized to be a multi-target kinase inhibitor. In experimental conditions, it has exhibited greater antileukemic potency than IM against CML cells. Most importantly, many in vitro and murine in vivo studies have confirmed that dasatinib is effective against a wide array of IM-resistant CML cells, except the T315I mutant. However, being a relatively new drug, dasatinib’s mechanism of action in CML is not completely understood. In this issue of Leukemia and Lymphoma, Dumka et al. shed some light on the mechanism of action of dasatinib in CML [3]. In immunoblotting experiments, the authors show that dasatinib treatment of IM-sensitive and insensitive cells lead to a doseand time-dependent increase in p38 phosphorylation, which was associated with p38 kinase activation. Interestingly, under similar conditions, dasatinib leads to de-phosphorylation of Erk1/2 kinases. These results are fascinating because inhibition of p38 kinase activity by SB203580 or p38siRNA leads to reversal of dasatinib-mediated pro-apototic effects on CML cells. Furthermore, the suppressed colony forming properties of patient-derived primary leukemic progenitors by dasatinib is reversed by p38 inhibition. The present study by Dumka et al. adds to the growing literature on the critical role played by p38 MAPK in mediating the antileukemic actions of drugs against CML. Previously, it has been shown that activation of p38 is critical to the antileukemic actions of interferon-a [4], imatinib [5], and arsenic trioxide [6]. Therefore, p38 activation is not an exclusive signaling event of dasatinib in CML cells. As previously stated, dasatinib is effective against CML cells bearing imatinib-resistant mutations. Unfortunately, CML harboring T315I mutations are unresponsive to all commercially available therapies, including second-generation TKIs. That notion, however, was recently challenged by Jabbour et al. who showed that the survival of CML-mutants