IFI represents a common complication for allogeneic HSCT recipients. Aspergillus species is the most frequently detected agent in these patients, and aspergillosis is characterized by a high mortality rate. Conversely, autologous HSCT recipients rarely develop aspergillosis, and the attributable mortality rate is markedly lower. Candidemia was observed less often than aspergillosis among both allogeneic and autologous HSCT recipients; furthermore, there was no difference in either the incidence of or the attributable mortality rate for candidemia among recipients of the 2 transplant types.

TT genotype may indicate a need to reduce the dose of MTX during prolonged administration. Considering the high prevalence of homozygous individuals in the Italian population, pretreatment screening may be worthwhile.

The targeting of BCR-ABL, a hybrid oncogenic tyrosine (Y) kinase, does not eradicate chronic myeloid leukemia (CML)-initiating cells. Activation of ␤-catenin was linked to CML leukemogenesis and drug resistance through its BCR-ABLdependent Y phosphorylation and impaired binding to GSK3␤ (glycogen synthase kinase 3␤). Herein, we show that GSK3␤ is constitutively Y 216 phosphoactivated and predominantly relocated to the cytoplasm in primary CML stem/ progenitor cells compared with its balanced active/inactive levels and cytosolic/ nuclear distribution in normal cells. Under cytokine support, persistent GSK3␤ activity and its altered subcellular localization were correlated with BCR-ABL-dependent and -independent activation of MAPK and p60-SRC/GSK3␤ complex formation. Specifically, GSK3␤ activity and nuclear import were increased by imatinib mesylate (IM), a selective ABL inhibitor, but prevented by dasatinib that targets both BCR-ABL-and cytokine-dependent MAPK/p60-SRC activity. SB216763, a specific GSK3 inhibitor, promoted an almost complete suppression of primary CML stem/progenitor cells when combined with IM, but not dasatinib, while sparing bcr-abl-negative cells. Our data indicate that GSK3 inhibition acts to prime a pro-differentiative/apoptotic transcription program in the nucleus of IM-treated CML cells by affecting the ␤-catenin, cyclinD1, C-EBP␣, ATF5, mTOR, and p27 levels. In conclusion, our data gain new insight in CML biology, indicating that GSK3 inhibitors may be of therapeutic value in selectively targeting leukemia-initiating cells in combination with IM but not dasatinib.

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