Issue Archive

Chronic myelomonocytic leukemia (CMML) is a rare disease with poor prognosis, for which the only potentially curative treatment is allogeneic hematopoietic stem cell transplant (allo-HCT). The evidence base for deciding who, when, and how to perform allo-HCT is growing but remains underdeveloped. In this Special Report, an international panel of experts reviews current knowledge and provides recommendations for patient selection and transplant-regimen choices.

As we recognize and diagnose an increasing number of preleukemic hematological states, we need to reconsider previously accepted notions about progression to acute myeloid leukemia (AML). Hall and colleagues provide a review that focuses on 4 disparate preleukemic states and what is known about the mechanisms of progression to AML, highlighting stem cell intrinsic changes in transcription and splicing factors as well as extrinsic changes. The authors identified some common features, such as monosomy 7 and inflammation, suggesting a paradigm to help us understand this complex process.

Fitusiran is a novel, small interfering RNA oligonucleotide directed against antithrombin that is subcutaneously injected monthly. Kenet and colleagues report on an open label, before-after design, phase 3 trial for patients with hemophilia A or B, with or without inhibitors, comparing fitusiran with a bypassing agent or clotting factor prophylaxis, respectively. Fitusiran reduces bleeding events significantly but may increase thrombotic events. These data suggest fitusiran could provide a new treatment option for some patients.

Biallelic loss-of-function germ line variants in the DNA damage repair gene nibrin (NBN) cause Nijmegen breakage syndrome, which carries an increased risk of childhood acute lymphoblastic leukemia (ALL). By studying a cohort of >4000 patients with ALL, Escherich et al reveal that deleterious heterozygous germ line variants in NBN result in a loss of protein stability and are associated with an increased risk of pediatric B-cell ALL. The authors’ findings further our knowledge of germ line predisposition for sporadic cases of childhood ALL and will prompt the search for more predisposition genes.

Avoiding immune destruction is a key evasion strategy acquired by leukemic cells. Fumero et al show that activating the histone demethylase PHF8 can trigger cell-intrinsic immune responses and specifically target acute myeloid leukemia (AML) cells. Pharmacologically induced PHF8 phosphorylation activated RNA sensors, triggering an interferon response. This study opens the possibility of targeting PHF8 as a new immunotherapy modality for AML.

Our knowledge of how erythropoiesis is so exquisitely coordinated remains incomplete. Using various strategies, Liu et al report on the acceleration of erythroid differentiation and reduction of fetal hemoglobin expression after depletion of a GATA2 gene–associated antisense long noncoding RNA (GATA2AS) in both erythroid cell lines and primary human erythroblasts. This occurs through modulation of several transcription factors and chromosome accessibility.