The molecular chaperone Hsp70 has been implicated in multiple stages of cancer development. In these processes, a co-chaperone Bag3 links Hsp70 with signaling pathways that control cancer development. Recently, we showed that besides affecting cancer cells, Hsp70 can also regulate the motility of macrophages and their tumor infiltration. However, the mechanisms of these effects have not been explored. Here, we demonstrated that the Hsp70-bound co-chaperone Bag3 associates with a transcription factor LITAF that can regulate the expression of inflammatory cytokines and chemokines in macrophages. Via this interaction, the Hsp70–Bag3 complex regulates expression levels of LITAF by controlling its proteasome-dependent and chaperone-mediated autophagy-dependent degradation. In turn, LITAF regulates the expression of the major chemokine CSF1, and adding this chemokine to the culture medium reversed the effects of Bag3 or LITAF silencing on the macrophage motility. Together, these findings uncover the Hsp70–Bag3–LITAF–CSF1 pathway that controls macrophage motility and tumor infiltration.

Finding synergistic drug combinations is an important area of cancer research. Here, we sought to rationally design synergistic drug combinations with an inhibitor of BTK kinase, ibrutinib, which is used for the treatment of several types of leukemia. We (a) used a pooled shRNA screen to identify genes that protect cells from the drug, (b) identified protective pathways via bioinformatics analysis of these gene sets, and (c) identified drugs that inhibit these pathways. Based on this analysis, we established that inhibitors of proteasome and mTORC1 could synergize with ibrutinib both in vitro and in vivo. We suggest that FDA-approved inhibitors of these pathways could be effectively combined with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL).

Chronic myeloid leukemia is an adult leukemia, constituting 15 % of all leukemia diagnoses. The fundamental driver of disease pathogenesis is the Bcr/Abl fusion protein, characterized by dysregulated tyrosine kinase activity. Abl kinase inhibitors have become the mainstay of treatment, however, patients often develop resistance due to genetic alterations, particularly affecting the Bcr/Abl oncoprotein. The tumor microenvironment is also associated with acquired resistance to Abl kinase inhibitors in chronic myeloid leukemia. The influence of hypoxic conditions on the development of chemoresistance to certain Abl kinase inhibitors was investigated in chronic myeloid leukemia. This study showed that hypoxia increased resistance to crizotinib, while imatinib resistance was modest. Both drugs effectively inhibited Bcr/Abl activity. Interestingly, the JAK1/2 inhibitor ruxolitinib further enhanced chemoresistance to crizotinib under hypoxic conditions. Hypoxia-inducible factor 1α (HIF1α) overexpression in JAK2 knockdown experiments confirmed their cooperative role in mediating crizotinib resistance. In addition, 2-methoxyestradiol, a non-estrogenic estradiol metabolite, restored crizotinib sensitivity under hypoxia and the combination of 2-methoxyestradiol with a JAK2 inhibitor showed promising results in overcoming crizotinib resistance. In summary, this study shows the critical role of selective targeting of components of the HIF1α signaling pathway for the complete eradication of chronic myeloid leukemia cells.