Huaier extract enhances the treatment efficacy of imatinib in Ik6+ Ph+ acute lymphoblastic leukemia.

Philadelphia chromosome-positive (Ph+) is considered as a high risk of acute lymphoblastic leukemia (ALL). Tyrosine kinase inhibitors (TKIs) are tailored drug for Ph+ ALL, but Ik6 is associated with TKI resistance and poor outcome of Ph+ ALL. In the present study, we investigated the potential benefit of combination therapy with imatinib and Huaier extract, a traditional Chinese medicine, in Ik6+ Ph+ ALL. The Ik6+ Ph+ -ALL cell lines Sup-B15 or BV173 were treated with Huaier extract, imatinib or the combination of the two. Analysis of cell proliferation showed that the combined treatment of imatinib and Huaier extract exhibited a greater effect on cell inhibition. Using flow cytometry and Western blot, enhanced effects on the induction of cell apoptosis were observed. The combination of the two drugs also exhibited a significant effect in decreasing the protein and enzymatic activity levels of BCR-ABL. The molecular mechanisms may be involved in BCR-ABL related pathways, including the inactivation of p-AKT, p-STAT5, p-mTOR and p-Lyn. Consistent with the in vitro results, the combination of Huaier extract and imatinib inhibit the growth and infiltration of xenografted tumors. Taken together, our findings show that Huaier extract enhances the anticancer efficacy of imatinib in Ik6+ Ph+ ALL Further, it also provides a potential clinical application in the treatment of refractory Ph+ ALL.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1.

We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.

Exploring the enkephalinergic differentiation potential in adult stem cells for cell therapy and drug screening implications.

Stem cell therapy is one of the most promising treatments in neuroregenerative medicine. Considering the role of the endogenous opioid system in controlling the pathophysiology of neurological disorders and behavioral aberrations, current studies have focused on enkephalins as a part of the opioid system. Due to high capability of unrestricted somatic stem cells (USSCs) and human mesenchymal stem cells (hMSCs) for cell therapy and transplantation; here, we examined their enkephalinergic differentiation potential through Ikaros-related pathways in order to develop in vitro models to help drug screening and stem cell therapy for the opioid-related disorders. The authenticity of the stem cells was verified by differentiation experiments along with flow cytometry for surface markers. Later, we confirmed their neurogenic differentiation with semiquantitative and quantitative transcriptional and translational evaluations of the enkephalinergic-related genes such as proenkephalin, CREBZF, Ikaros, and prodynorphin. Our findings supported the enkephalinergic differentiation of these stem cells. Noteworthy, USSCs showed higher potential for differentiating into enkephalinergic neurons under Ikaros activation than hMSCs, which makes them appropriate for neurological therapeutic applications. In conclusion, this study suggests a powerful in vitro model for neurogenesis that may help clarification of enkephalinergic differentiation and related signaling networks along with neural drug screening. Such investigations may be beneficial to ameliorate the neural-related therapeutic approaches.

Ikaros expression in tongue sole macrophages: a marker for lipopolysaccharide- and lipoteichoic acid-induced inflammatory responses.

Ikaros, an important transcription factor plays a role in the development of hemato-lymphoid system, yet its functional importance in fish macrophages remains unknown. In this study, an Ikaros cDNA was cloned from the half-smooth tongue sole Cynoglossus semilaevis. The cDNA contained an open reading frame of 1,290 nucleotides that encoded a 430 amino acid protein. The deduced protein is structurally similar to dul from other species, for example human, axolotl, and possesses 3-zinc finger and 2-zinc finger domains at its N- and C-termini, respectively. Phylogenetic analysis revealed C. semilaevis Ikaros to be grouped with all the fish Ikaros, but branching from other Ikaros family members. Both semi-quantitative PCR and quantitative real-time PCR indicated Ikaros to be predominantly expressed in the immune-relevant tissues such as kidney, thymus, spleen and liver. In the macrophages cultured from C. semilaevis head kidney and challenged with lipopolysaccharide and lipoteichoic acid not only induced expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin 1-beta but also caused up-regulation of Ikaros in a dose- and time-dependent fashions. All these data suggest that Ikaros might be a useful marker for inflammatory responses in C. semilaevis.