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BLOOD COMMENTARIES

CLINICAL TRIALS AND OBSERVATIONS

Shah et al report results of a phase 1 trial of KTE-X19 anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in 45 adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Complete remissions, all of which were minimal residual disease negative, were achieved in 69% of patients, and in 83% of patients receiving the highest dose, which is the dose in the ongoing phase 2 trial.

HEMATOPOIESIS AND STEM CELLS

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Cytomegalovirus (CMV) infection is a major complication of hematopoietic cell transplantation (HCT), and decreased CMV-specific T-cell response increases the risk of late CMV disease. Zamora et al report that although letermovir prophylaxis decreases early CMV infection, it also leads to decreased CMV-specific T-cell immunity when compared to polymerase chain reaction–guided preemptive therapy with ganciclovir, increasing the risk for late CMV reactivation.

LYMPHOID NEOPLASIA

Inhibition of the B-cell receptor (BCR) pathways with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitors has transformed treatment of chronic lymphocytic leukemia. Whereas resistance to the BTK inhibitor ibrutinib is often mediated by mutations in BTK or the immediate downstream protein PCGL2, Murali and colleagues report that resistance to the PI3Kδ inhibitor idelalisib is associated not with mutations in PI3Kδ, but rather with mutations in the mitogen-activated protein kinase (MAPK) pathway, suggesting that MAPK inhibitors could restore idelalisib sensitivity.

The infiltration of follicular lymphoma (FL) cells from lymph nodes into the bone marrow (BM) is dependent on a permissive BM microenvironment. Dumontet et al demonstrate that extracellular vesicles derived from FL tumor cells activate BM stromal cells within the hematopoietic stem cell niche and modulate their gene expression profile to render them supportive of FL cell infiltration.

MYELOID NEOPLASIA

RNA-binding proteins (RBPs) regulate gene expression by modulating transcription, translation, posttranslational modification, and RNA stability. Feng et al demonstrate that YBX1 is an RBP that is upregulated in AML cells, where it interacts with and stabilizes m6A-tagged RNA, including BCL2 and MYC. YBX1 deletion induces messenger RNA decay of MYC and BCL2 transcripts and increases differentiation and apoptosis in mouse AML and in human primary AML cells without any effect on normal hematopoietic stem cells, suggesting a potential novel pathway to target in leukemic stem cells.

PLATELETS AND THROMBOPOIESIS

THROMBOSIS AND HEMOSTASIS

Thrombolysis is the only approved therapy for acute ischemic stroke, but its success is limited by secondary hemorrhage. Wang and colleagues report that infusion of tissue plasminogen activator (tPA) in a murine stroke model results in increased neutrophil extracellular trap (NET) formation. NETs disrupt the blood-brain barrier and increase brain hemorrhage that can be decreased by DNase I or inhibition of NET production. Targeting NETs could improve the safety of tPA administration for stroke.

BLOOD WORK

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