Parvovirus B19-associated graft failure after allogeneic hematopoietic stem cell transplantation.

Background: Parvovirus B19 (PVB19) infection has been implicated in allograft failure or dysfunction in solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the literature is limited.

Case: Two pediatric patients were diagnosed with PVB19 infection around the time of allo-HSCT graft failure. Both cases were secondary graft failure and required second allo-HSCT.

Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials.

Introduction: The phase 2 POPLAR and phase 3 OAK studies of the anti-programmed death-ligand 1 (PD-L1) immunotherapy atezolizumab in patients with previously treated advanced NSCLC revealed significant improvements in survival versus docetaxel (p = 0.04 and 0.0003, respectively).

Atezolizumab Treatment Beyond Progression in Advanced NSCLC: Results From the Randomized, Phase III OAK Study.

Introduction: Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti-programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP).

Patient-Reported Outcomes in OAK: A Phase III Study of Atezolizumab Versus Docetaxel in Advanced Non-Small-cell Lung Cancer.

Background: The randomized phase III OAK (a study of atezolizumab compared with docetaxel in participants with locally advanced or metastatic non-small-cell lung cancer [NSCLC] who have failed platinum-containing therapy) trial investigated the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab for advanced or metastatic, previously treated, NSCLC. Atezolizumab significantly improved overall survival (OS) compared with docetaxel (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.

Updated Efficacy Analysis Including Secondary Population Results for OAK: A Randomized Phase III Study of Atezolizumab versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer.

Introduction: The efficacy and safety of atezolizumab versus the efficacy and safety of docetaxel as second- or third-line treatment in patients with advanced NSCLC in the primary (n = 850) and secondary (n = 1225) efficacy populations of the randomized phase III OAK study (respectively referred to as the intention-to-treat [ITT] 850 [ITT850] and ITT1225) at an updated data cutoff were assessed.

Methods: Patients received atezolizumab, 1200 mg, or docetaxel, 75 mg/m, intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary end point was overall survival (OS) in the ITT population and programmed death-ligand 1-expressing subgroup.

Next-generation NAMPT inhibitors identified by sequential high-throughput phenotypic chemical and functional genomic screens.

Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells.

Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing.

Runx1 is expressed in skeletal elements, but its role in fracture repair has not been analyzed. We created mice with a hypomorphic Runx1 allele (Runx1(L148A) ) and generated Runx1(L148A/-) mice in which >50% of Runx1 activity was abrogated. Runx1(L148A/-) mice were viable but runted.

GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.

Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.

Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.

The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional subprogram more akin to that of embryonic stem cells (ESCs) than to that of adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3, and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when coexpressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia-initiating MLL/Hox/Meis program.

Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles.

Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML). Sporadic mono- and biallelic mutations are found at high frequencies in AML M0, in radiation-associated and therapy-related myelodysplastic syndrome and AML, and in isolated cases of AML M2, M5a, M3 relapse, and chronic myelogenous leukemia in blast phase. Mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD).

Runx1 is expressed in adult mouse hematopoietic stem cells and differentiating myeloid and lymphoid cells, but not in maturing erythroid cells.

The transcription factor Runx1 marks all functional hematopoietic stem cells (HSCs) in the embryo and is required for their generation. Mutations in Runx1 are found in approximately 25% of acute leukemias and in familial platelet disorder, suggesting a role for Runx1 in adult hematopoiesis as well. A comprehensive analysis of Runx1 expression in adult hematopoiesis is lacking.

Energetic contribution of residues in the Runx1 Runt domain to DNA binding.

Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in hematopoiesis and in the development of bone, stomach epithelium, and proprioceptive neurons. Mutations in CBF genes are found in leukemias, bone disorders, and gastric cancer. CBFs consist of a DNA-binding CBF alpha subunit and a non-DNA-binding CBF beta subunit.