Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis

B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)–only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1–Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2

Post-transplant multimorbidity index and quality of life in patients with chronic graft-versus-host disease—results from a joint evaluation of a prospective German multicenter validation trial and a cohort from the National Institutes of Health

Comorbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT) impairs quality of life (QoL), physical functioning, and survival. We developed a new standardized measure to capture comorbidity after transplantation, the Posttransplant Multimorbidity Index (PTMI) in a cohort of 50 long term survivors. We subsequently evaluated the content validity and impact on survival and QoL within a multicenter trial, including 208 patients (pts) after alloHSCT, who were prospectively evaluated applying the FACT-BMT, the Human Activity Profile (HAP), the SF-36 v.2, PTMI and the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). The most prevalent comorbidities were compensated arterial hypertension (28.4%), ambulatory infections (25.5%), iron overload (23%), mild renal function impairment (20%), and osteoporosis (13%). Applying the PTMI 13% of patients had no comorbidity, while 37.1% had 1–3 comorbidities, 27.4% had 4–6 comorbidities, and 13.5% had > 6 comorbidities. Chronic graft-versus-host disease (cGvHD) was significantly associated with the PTMI, while age and prior acute GvHD were not. In contrast, the HCT-CI was not associated with the presence of cGvHD. cGvHD was significantly associated with depression (r = 0.16), neurological disease (r = 0.21), osteoporosis (r = 0.18) and nonmelanoma skin cancer (r = 0.26). The PTMI demonstrated strong measurement properties and compared to the HCT-CI captured a wider range of comorbidities associated with cGvHD

Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Long-term survival after allogeneic hematopoietic stem cell transplantation requires an intact immunosurveillance, which howeverbut is hampered by conditioning therapy-associated lymphoid organ damage associated with conditioning therapy, by graft-versus-host disease and by immunosuppression. Our study aimed at identifying mechanisms contributing to sustained low memory B-cell numbers deficiency post-transplant. Peripheral B- and T-cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to one year post-transplant. Apoptosis of B cells after CpG/CD40L/PMA/ionomycinBCR-independent and dependent stimulation and drug-efflux capacity were analysed. Half the patients suffered from infections post day 180. All patients were lackinghad strongly diminished CD27(+) memory B cells despite already normalized total B-cell numbers and fully-recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B-cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon T-cellCD40/TLR-9 dependent activation, B cells underwent significantly increased apoptosis (healthy 15±2%, patients 60±6%; p≤0.001) paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B-cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9 dependent activation. Drug-efflux capacity of naïve B cells was diminished in Cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that sustained B-cell survival, migration and T-cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on cellular level and should address the long-term sequela of B-cell defects post-transplant

Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells

Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti-viral adaptive responses. However, the viral ligand that drives the activation and differentiation of adaptive NKG2C+NK cells has remained unclear. Here we found that adaptive NKG2C+NK cells differentially recognized distinct HCMV strains encoding variable UL40 peptides that, in combination with pro-inflammatory signals, controlled the population expansion and differentiation of adaptive NKG2C+NK cells. Thus, we propose that polymorphic HCMV peptides contribute to shaping of the heterogeneity of adaptive NKG2C+NK cell populations among HCMV-seropositive people

Erratum : Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

This corrects the article DOI: 10.1038/nm.4484