Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia1-3. We report that Autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and required for a timely onset of Gli2-induced skin tumorigenesis in mice. Induction of Aire mRNA in keratinocytes depends upon a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K4. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each are bound to a specific promoter region featuring a NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent pro-inflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.

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SUMMARY Keratins—types I and II—are the intermediate-filament-forming proteins expressed in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type–, differentiation-, and context-dependent manner. Here, we review how keratins serve multiple homeostatic and stress-triggered mechanical and nonmechanical functions, including maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications and keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility or altered tissue homeostasis. Furthermore, keratin mutation or misregulation represents risk factors or genetic modifiers for several additional acute and chronic diseases.

Cohesins are important for chromosome structure and chromosome segregation during mitosis and meiosis. Cohesins are composed of two structural maintenance of chromosomes (SMC1-SMC3) proteins that form a V-shaped heterodimer structure, which is bridged by a α-kleisin protein and a stromal antigen (STAG) protein. Previous studies in mouse have shown that there is one SMC1 protein (SMC1β), two α-kleisins (RAD21L and REC8) and one STAG protein (STAG3) that are meiosis-specific. During meiosis, homologous chromosomes must recombine with one another in the context of a tripartite structure known as the synaptonemal complex (SC). From interaction studies, it has been shown that there are at least four meiosis-specific forms of cohesin, which together with the mitotic cohesin complex, are lateral components of the SC. STAG3 is the only meiosis-specific subunit that is represented within all four meiosis-specific cohesin complexes. In Stag3 mutant germ cells, the protein level of other meiosis-specific cohesin subunits (SMC1β, RAD21L and REC8) is reduced, and their localization to chromosome axes is disrupted. In contrast, the mitotic cohesin complex remains intact and localizes robustly to the meiotic chromosome axes. The instability of meiosis-specific cohesins observed in Stag3 mutants results in aberrant DNA repair processes, and disruption of synapsis between homologous chromosomes. Furthermore, mutation of Stag3 results in perturbation of pericentromeric heterochromatin clustering, and disruption of centromere cohesion between sister chromatids during meiotic prophase. These defects result in early prophase I arrest and apoptosis in both male and female germ cells. The meiotic defects observed in Stag3 mutants are more severe when compared to single mutants for Smc1β, Rec8 and Rad21l, however they are not as severe as the Rec8, Rad21l double mutants. Taken together, our study demonstrates that STAG3 is required for the stability of all meiosis-specific cohesin complexes. Furthermore, our data suggests that STAG3 is required for structural changes of chromosomes that mediate chromosome pairing and synapsis, DNA repair and progression of meiosis.

clinicaltrials.gov Identifier: NCT01371630.

Background The outcome of patients with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their additions to low-intensity chemotherapy may further improved outcomes in ALL in first relapse. Methods The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD. Inotuzumab was given on Day 3 of each of the first 4 cycles at 1.8–1.3 mg/m2 for cycle 1 followed by 1.3–1.0 mg/m2 for subsequent cycles. From Patient #39 and onwards, inotuzumab dose was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during Cycle 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent cycles), and blinatumomab for up to 4 cycles after inotuzumab therapy was administered. Results Forty-eight patients with Philadelphia chromosome-negative ALL in first relapse with a median age of 39 years were treated. Overall, 44 patients (92%) responded, 35 of them (73%) achieving complete response. The overall MRD negativity rate among responders was 93%. Twenty-four patients (50%) received ASCT. Veno-occlusive disease (VOD) of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median PFS and OS were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients are alive [13 (54%) in remission]. Of the remaining 20 responding patients who did not receive subsequent ASCT, 6 (30%) remain in remission at the last follow-up. Using the propensity score matching, the combination of mini-HCVD and inotuzumab +/− blinatumomab conferred better outcome than intensive salvage chemotherapy or inotuzumab alone. Conclusions The combination of inotuzumab with low-intensity mini-hyper-CVD chemotherapy +/− blinatumomab shows encouraging results in patients with ALL in first salvage. Trial Registration Clinicaltrials.gov Identifier

Background The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)‐negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low‐intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low‐intensity chemotherapy (mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone [mini‐HCVD]) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen. Methods The authors analyzed 135 older patients with newly diagnosed, Ph‐negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method. Results Propensity score matching identified 38 patients in each cohort. The antibody plus low‐intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3‐year event‐free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3‐year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini‐HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival. Conclusions The combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph‐negative ALL and confers a better outcome compared with standard HCVAD chemotherapy.

Previously thought to reside exclusively in the cytoplasm, the cytoskeletal protein keratin 17 (K17) has been recently identified inside the nucleus of tumor epithelial cells with a direct impact on cell proliferation and gene expression. We comment on fundamental questions raised by this new finding and the associated significance. Everything should be made as simple as possible, but not simpler.Albert Einstein