Issue Archive

Krenn and Aberger review the role of Hedgehog (HH)/GLI signaling in hematopoiesis and its contribution to hematologic malignancies. The authors review molecular mechanisms by which HH/GLI signaling contributes to oncogenesis and review the current state-of-the-art of HH inhibitors as treatment for hematologic malignancy.

Loo et al report the results of a phase 2, placebo-controlled study of adding sorafenib to intensive induction chemotherapy for patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). The authors report that event-free survival and overall survival were not improved by sorafenib in this setting. However, the study suggests that sorafenib may improve survival in those patients undergoing transplant in first remission; a larger study would be required to confirm this.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by cytotoxic T-cell and natural killer cell–dysfunction. Shim and colleagues investigated the B-cell compartment in active HLH, demonstrating marked suppression of early B-cell development. The authors show decreased emergence of class-switched memory B cells (CSMB) and decreased plasma cell maturation in active HLH, associated with a decrease in circulating T follicular helper (cTfh) cells. The profile is ameliorated with control of the T-cell activation with increases in CSMB and cTfh. Further study is needed to determine whether the B-cell compartment fully recovers with control of HLH.

Wimberger and colleagues explore the role of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) in promoting lymphomagenesis. Constitutive MALT1 (paracaspase 1) activity drives survival of lymphoma cells through both proteolytic and nonproteolytic pathways that have an impact on transcriptional activation and posttranscriptional modifications of gene expression. The authors identify mediators of these pathways that can be biomarkers of divergent effects of MALT1 inhibitors.

Acute myeloid leukemia (AML) with TP53 mutation has a poor prognosis. Man et al performed an in silico analysis of differential gene expression in TP53-mutant AML and identified pololike kinase 4 (PLK4) as a potential novel therapeutic target. PLK4 expression is increased in TP53-mutant AML, while it is suppressed by activated p53 signaling in TP53 wild-type AML. PLK4 inhibition suppresses TP53-mutant AML cell growth through histone modification and activation of immune response, suggesting PLK4 inhibition as a potential novel therapy for this poor prognosis AML.

Baro and colleagues report that red cell CD44 acts as a coreceptor for 2 invasion ligands important for erythrocyte invasion by Plasmodium falciparum. The authors used gene editing to create CD44-null erythrocytes that yielded cells that are partially resistant to P falciparum invasion. They demonstrate that CD44 binds to antigens implication in P falciparum invasion and that the parasite stimulates CD44-dependent phosphorylation of cytoskeletal proteins, altering red cell deformability and enhancing invasion.