Issue Archive

Primary vitreoretinal lymphoma (PVRL) is a rare variant of central nervous system (CNS) lymphoma that arises in the eye without initial brain involvement. Soussain et al review the challenges of diagnosis and treatment of PVRL. Although local therapy preserves vision, 56% to 90% of patients develop CNS relapse. Approaches to primary and secondary therapy are discussed.

MYD88 is mutated over 90% of patients with Waldenström macroglobulinemia (WM), where it enhances Bruton tyrosine kinase (BTK)-related signaling, which can be targeted by BTK inhibitors, including ibrutinib. Concomitant CXCR4 mutations, found in 30% to 40% of WM patients, promote BTK resistance. Treon et al report that in a phase 1 trial of the CXCR4 antagonist ulocuplumab in combination with ibrutinib in CXCR4-mutant WM, therapy was well tolerated, with excellent response rates and a 2-year progression-free survival rate of 90%.

In the switch from fetal to adult globin production, γ-globin expression is repressed by BCL11A and LRF/ZBTB7A, transcriptional repressors that bind the γ-globin promoter at distinct sites. Psatha and colleagues investigated the effect on γ-globin expression of combined mutation of the 2 binding sites with and without mutation of the BCL11A enhancer region. Mutating both binding sites decreases fetal hemoglobin (HbF) more than mutating either alone; however, combining mutation of either site with disruption of the BCL11A enhancer greatly increases HbF. This suggests that combining mutations may increase the clinical benefit of gene therapy for β-globin hemoglobinopathies.

Glycosylation of the surface immunoglobulin (sIg) variable region in follicular lymphoma has been previously described. Chiodin and colleagues report that the same modification is seen in a subset of diffuse large B-cell lymphomas (DLBCLs), occurring in about 50% of GCB-type, but only 6% of ABC-type DLBCLs and conferring poor prognosis. The modification facilitates antigen-independent signaling B-cell receptor activation through interactions with microenvironmental lectins that can be specifically targeted with antibody. Thus, this modification identifies an aggressive form of DLBCL that may be targeted therapeutically.

It has been challenging to understand the pathophysiology that distinguishes between light-chain amyloidosis (AL) and multiple myeloma (MM), 2 plasma cell (PC) malignancies with strikingly different clinical presentations. In this month's CME article, Alameda et al define a “transcriptional atlas” of normal PCs, AL amyloidosis, MM, and monoclonal gammopathy of uncertain significance, identifying 13 different transcriptional patterns linking distinct PC dyscrasias to subsets of normal developing PCs, with diagnostic and prognostic implications.

Systemic mastocytosis (SM) is a KIT-driven hematopoietic neoplasm with a wide range of aggressiveness. Agopian et al analyzed plasma metabolomic profiles of patients with SM and identified N-acetyl-D-glucosamine (GlcNAc) as a powerful predictor of SM severity, suggesting a potential targetable pathway for treatment.

Inactivating mutations in EZH2 are seen in myeloproliferative neoplasms, especially in association with myelofibrosis. Mazzi and colleagues used small molecules and short hairpin RNA to demonstrate a dual role for EZH2 in megakaryopoiesis. EZH2 downmodulates early megakaryocytic differentiation, and inhibition accelerates lineage commitment without increasing proliferation. However, it enhances megakaryocyte maturation, and its inhibition in late stages blocks maturation and decreases proplatelet formation.

Studies aimed at identifying genetic factors predisposing to cytomegalovirus (CMV) infection following hematopoietic cell transplantation (HCT) have varied widely and have not been validated. Casto and colleagues report a study of 117 previously reported variants in donor and recipient pairs of more than 2000 CMV-positive HCT recipients. Of the 117 candidate genes, they implicate only ABCB1, which encodes P-glycoprotein, in CMV reactivation. The gene variant results in reduced efflux of calcineurin inhibitors from donor lymphocytes, likely exerting its effect by increasing immune suppression.