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A. Tobio et al.
of STAT5 and PI3K/AKT pathways may be desirable to treat patients with mastocytosis and elevated IL-6, as was proposed for drug-resistant chronic myelogenous leukemia where both pathways are critical for disease evolution.44 Alternatively, since small molecule inhibitors for JAK2 such as fedratinib and the dual JAK1/2 inhibitor ruxolitinib inhibit STAT5 activity and IL-6 upregulation in neoplastic mast cells (Figures 4 and 6), and both drugs are approved by the US Federal Drug Administration for var- ious blood disorders, they are also feasible drug candi- dates alone or in combination with other therapies for increased therapeutic index.
The work presented here links expression of the D816V- KIT variant with IL-6 persistent activation in mast cells and sheds light into the molecular mechanisms driving dysregulated IL-6. Our data underscore a role for constitu- tive STAT5 activation, achieved by both JAK2 and ERK-
mediated activities, and PI3K/AKT signals on IL-6 dysreg- ulation. Together, our findings establish the groundwork for exploring new potential therapeutic combinations tar- geting the mentioned kinases in the treatment of patients with mastocytosis.
Acknowledgments
We thank Robin Eisch in her role as protocol study coordinator, Linda Scott, the nurse practitioner on the study protocols, Pahul Hanjra and Irina Maric for providing information on patients and Daly Cantave for arranging for patient bone marrow sam- ples.
Funding
This work was supported by the Division of Intramural Research within the National Institute of Allergy and Infectious Diseases (NIAID), at the National Institutes of Health.
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