Issue Archive

In a Plenary Paper, Zhen and colleagues provide novel molecular insights into the requirement for Runx1 in a mouse model of inversion(16) acute myeloid leukemia (AML). They challenge the prevailing RUNX1 repression model of this disease, showing that RUNX1 and CBFβ-SMMHC mainly function together as activators of gene expression through direct target gene binding and that RUNX1 is indispensable for inversion(16) AML development. These insights should facilitate the development of therapeutics that target RUNX1/CBFβ-SMMHC interaction.

In this timely review, Steinberg explores new insights into the genetic and biological basis of variations in fetal hemoglobin and its ameliorating influence on sickle cell disease (SCD). This framework enables a discussion of past and current clinical trials of cell-based therapeutics, including gene editing approaches, that may portend curative treatment regimens for SCD.

Bartlett et al report the early-phase safety and efficacy of a 2-agent 3-pronged immunotherapy regimen targeting specific immunologic characteristics of Hodgkin lymphoma. AFM13 is a bispecific antibody engaging Hodgkin and Reed Sternberg (HRS) cells via CD30 and natural killer (NK) cells via CD16A. In combination with pembrolizumab to relieve the blockade by PD-L1 of NK cell activity, response rates exceeded 80%, with complete metabolic responses in 46% of patients.

BET (bromodomain and extraterminal motif) proteins play an important role in the epigenetic regulation of hematopoietic stem cell (HSC) maintenance in mice. Hua at al demonstrate that adding the BET inhibitor CPI203 to a cytokine cocktail expands serially transplantable human cord blood HSCs and enhances their potential to differentiate into megakaryocytes.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia and ocular and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides. In this month’s CME article, Le Cann et al report a large series of this very rare syndrome, revealing that one-third of patients harbor an overt hematological malignancy such as Waldenström macroglobulinemia and suggesting that intravenous Ig and rituximab-based regimens are effective therapies.

Dzama and colleagues explored the preclinical potential of combining small-molecule inhibitors that disrupt a key protein-protein interaction maintaining the stem cell state with established inhibitors of FLT3 kinase in NPM1-mutant and KMT2A-rearranged leukemias. They demonstrate enhanced differentiation and reduced proliferation with the combination and improved in vivo efficacy.

Congenital erythropoietic porphyria (CEP) is an autosomal disorder of heme synthesis in which the buildup of phototoxic metabolites in red cells leads to disfiguring skin lesions and hemolysis. Blouin et al provide a mechanistic basis for iron chelation to reduce porphyrin accumulation in this debilitating disease and demonstrate reversal of hemolytic anemia and skin photosensitivity in CEP mice. This study paves the way for clinical trials of this approach.