Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia.

Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioma cell invasion through induction of NF-κB-inducing kinase (NIK) and noncanonical NF-κB signaling.

BACKGROUND: High-grade gliomas are one of the most invasive and therapy-resistant cancers. We have recently shown that noncanonical NF-κB/RelB signaling is a potent driver of tumorigenesis and invasion in the aggressive, mesenchymal subtype of glioma. However, the relevant signals that induce activation of noncanonical NF-κB signaling in glioma and its function relative to the canonical NF-κB pathway remain elusive. METHODS: The ability of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) to regulate NF-κB signaling and promote tumor progression was investigated in both established and primary high-grade glioma tumor lines using a three-dimensional (3-D) collagen invasion assay. The roles of specific NF-κB proteins in regulating glioma cell invasion and expression of Matrix Metalloproteinase 9 (MMP9) in response to TWEAK were evaluated using shRNA-mediated loss-of-function studies. The ability of NF-κB-inducing kinase (NIK) to promote glioma growth in vivo was investigated using an orthotopic xenograft mouse model. RESULTS: In glioma cells that display elevated noncanonical NF-κB signaling, loss of RelB attenuates invasion without affecting RelA expression or phosphorylation and RelB is sufficient to promote invasion in the absence of RelA. The cytokine TWEAK preferentially activates the noncanonical NF-κB pathway through induction of p100 processing to p52 and nuclear accumulation of both RelB and p52 without activating the canonical NF-κB pathway. Moreover, TWEAK, but not TNFα, significantly increases NIK mRNA levels. TWEAK also promotes noncanonical NFκB-dependent MMP9 expression and glioma cell invasion. Finally, expression of NIK is sufficient to increase gliomagenesis in vivo. CONCLUSIONS: Our data establish a key role for NIK and noncanonical NF-κB in mediating TWEAK-induced, MMP-dependent glioma cell invasion. The findings also demonstrate that TWEAK induces noncanonical NF-κB signaling and signal-specific regulation of NIK mRNA expression. Together, these studies reveal the important role of noncanonical NF-κB signaling in regulating glioma invasiveness and highlight the therapeutic potential of targeting activation of NIK in this deadly disease.

Akt, 14-3-3ζ, and vimentin mediate a drug-resistant invasive phenotype in diffuse large B-cell lymphoma.

Development of resistance to the CHOP chemotherapeutic regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) remains a major cause of treatment failure and mortality in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL). We established CHOP-resistant DLBCL cells as a model system to investigate molecular mechanisms involved in multidrug resistance. Two-dimensional differential in-gel (DIGE) analysis identified 10 differentially expressed proteins between CHOP-sensitive and -resistant DLBCL cells that play roles in glycolysis (triosephosphate isomerase-1, enolase-1), cytoskeletal structure (ezrin, vimentin, tubulin-specific chaperone B), purine biosynthesis (serine hydroxymethyltransferase), calcium binding (sorcin), and apoptosis (p53, 14-3-3ζ, Akt). Akt, 14-3-3ζ, and vimentin were up-regulated in CHOP-resistant DLBCL cells. We showed previously that siRNA-mediated knockdown of 14-3-3ζ reversed CHOP resistance in DLBCL cells (Maxwell et al., J Biol Chem 2009;284:22379-22389). Here we show that chemical inhibition of Akt overcomes CHOP resistance in DLBCL cells. CHOP-resistant cells exhibited a five-fold greater ability to invade collagen matrices compared with CHOP-sensitive cells. Knockdown of vimentin by siRNA or withaferin A repressed the invasiveness of CHOP-resistant cells in collagen matrices. Increased expressions of Akt, 14-3-3ζ, and vimentin were observed by Western blotting in primary DLBCL tissues relative to normal lymphatic tissue. The data implicate activation of an Akt-14-3-3ζ signaling pathway in promoting a multidrug-resistant phenotype associated with a vimentin-dependent invasive behavior in DLBCL cells.