Issue Archive

Retinoids are ligands for nuclear receptors that act as transcriptional switches. Geoffroy et al contribute an authoritative and timely review of retinoids in leukemia and hematopoiesis. They describe the scientific basis upon which these agents may be used in combination with established therapies for treatment of leukemias other than acute promyelocytic leukemia.

Fakhouri and colleagues report the first prospective study of treatment discontinuation in 55 patients with atypical hemolytic-uremic syndrome (aHUS) who had achieved remission with eculizumab. Relapse is more likely if there is a complement gene variant; however, most patients (77%) remain relapse free and eculizumab resumption reestablishes baseline renal function in the majority of relapsers. Cessation in remission is a safe and effective strategy associated with improved quality of life and cost savings.

Aluri et al report the discovery of a novel cause of immune dysregulation: inborn errors causing gain of function in Toll-like receptor 8 (TLR8). They provide the first description of pathogenic defects in TLR8 that are associated with development of chronic neutropenia, bone marrow failure, and associated immune deficiency with recurrent infections. Notably, 5 of 6 cases display mosaicism, indicating that the presence of a pathogenic variant in only 5% to 30% of cells is sufficent to cause disease.

Early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) is a high-risk subtype of T-cell ALL. Using single-cell RNA-sequencing, Anand and colleagues characterized a subset of NOTCH1-mutated ETP-ALL and its immune microenvironment and revealed distinct stem cell states, one that is fast cycling and Notch activation dependent and another that is slow cycling and Notch independent. They also show that leukemic cells modulate a dysfunctional CD8⁺ T-cell immune response, apparently through expression of galectin-9. Collectively, these data provide some insights to this leukemia’s propensity to resist induction therapy or to relapse.

Deregulation of B-cell receptor (BCR) signaling and CD40-mediated T-cell interactions within the lymph node microenvironment are pivotal to chronic lymphocytic leukemia (CLL) pathogenesis. Sharma et al performed expression profiling of CLL cells recently emigrated from nodes to identify a BCR signaling–repressible microRNA, miR-29, that acts as a negative regulator of CD40 responsiveness. These data indicate that microRNAs can act to coordinate CLL responsiveness to T-cell signals and facilitate the co-occurrence of BCR and CD40 signaling activation.

Ghosh et al convincingly demonstrate the crucial role of the hypoxia-inducible transcription factor HIF-2 in murine models of 2 congenital polycythemias, Chuvash erythrocytosis and erythrocytosis due to mutation of iron-regulatory protein 1 (IRP1). Oral administration of a specific HIF-2α inhibitor normalizes the expression of HIF-2–regulated genes and corrects erythrocytosis and pulmonary hypertension in both models, suggesting potential therapeutic efficacy of such inhibitors in patients.

Activated factor VIII (FVIIIa) is rate limiting for factor X activity in hemostasis. Wilhelm and colleagues provide novel insights into the physiological role of activated protein C (APC) in FVIIIa regulation in vivo by generating FVIII mutants resistant to APC-mediated proteolysis. FVIII-QQ demonstrates superior hemostatic efficacy relative to wild-type FVIII in murine models. This raises the possibility of development of APC-resistant factor VIII for hemophilia replacement therapy or gene replacement therapy.