Table of Contents
CLINICAL TRIALS AND OBSERVATIONS
Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project
Clinical Trials & Observations
Angioimmunoblastic T-cell lymphoma (AITL) is a rare peripheral T-cell lymphoma with poor prognosis. Advani et al report on outcomes for 282 patients enrolled in the international prospective T-cell Project and develop a prognostic score for the disease. Prognosis remains poor, with 5-year overall survival of only 44%; outcomes are improved among those patients who undergo autologous stem cell transplantation, but only 13% of patients received transplants. More-effective therapeutic approaches are needed.
HEMATOPOIESIS AND STEM CELLS
The chromatin remodeler CHD8 governs hematopoietic stem/progenitor survival by regulating ATM-mediated P53 protein stability
Chd8 encodes a chromatin helicase DNA-binding (CHD) protein that is mutated in a subtype of autism spectrum disorder. Tu and colleagues report that CHD8 plays a necessary role in hematopoietic stem/progenitor cell (HSPC) proliferation and that Chd8-null mice have markedly reduced HSPCs, leading to anemia, pancytopenia, and engraftment failure. They demonstrate that CHD8 complexes with ATM and its loss drives genomic instability through changes in chromatin accessibility and stabilization of P53, leading to HSPC apoptosis.
IMMUNOBIOLOGY AND IMMUNOTHERAPY
The combination of venetoclax and the hypomethylating agent azacytidine induces a high rate of complete responses in treatment-naïve older patients with acute myeloid leukemia (AML). Lee and colleagues elucidate a novel mechanism of action for the synergy of these agents, demonstrating that venetoclax enhances reactive oxygen species (ROS) generation and enhances T-cell effector function while azacytidine renders AML cells more susceptible to T cell–mediated cytotoxicity.
AID overexpression leads to aggressive murine CLL and nonimmunoglobulin mutations that mirror human neoplasms
Morande et al report that overexpression of activation-induced deaminase (AID) in a mouse model of chronic lymphocytic leukemia (CLL) increases the rate of acquisition of secondary mutations and rapid progression of aggressive lymphoma. They further demonstrate that the AID-induced gene mutations mimic those seen in the progression of human CLL.
THROMBOSIS AND HEMOSTASIS
Plasmin-mediated cleavage of high-molecular-weight kininogen contributes to acetaminophen-induced acute liver failure
Henderson et al elucidate the role of high-molecular-weight kininogen (HK) in acetaminophen (APAP)-induced liver injury. HK-deficient mice are resistant to APAP-induced liver failure without changes in activation of anticoagulation. The authors demonstrate that plasmin-mediated HK cleavage contributes to APAP toxicity independently of thrombin generation or bradykinin signaling, revealing a novel pathway of HK-mediated inflammatory signaling that could be targeted to prevent APAP-induced liver toxicity.
HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis
Haploidentical transplantation owes its success to the use of posttransplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis, with results similar to matched unrelated donor (MUD) transplants using standard GVHD prophylaxis. However, in a comparison of 2036 haploidentical and 284 MUD transplant patients uniformly treated with PTCybased GVHD prophylaxis, Gooptu et al demonstrate that with reduced-intensity conditioning, results favor MUD transplants, with reduced graft failure, acute GVHD, and nonrelapse mortality and improved overall survival.
Hematoxylin and eosin–stained femur section of a Chd8−/− mouse. Loss of Chd8 causes bone marrow hypoplasia and resultant pancytopenia due to relaxed chromatin structure, elevated ATM activity, increased stability of P53 protein, and consequent apoptosis of bone marrow HSPCs. See the article by Tu et al on page 221.
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