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BLOOD COMMENTARIES

PERSPECTIVE

REVIEW SERIES

Routine use of next-generation sequencing of hematologic malignancies has greatly expanded the representation of hereditary predisposition syndromes among patients with leukemia. Introduced by Associate Editor Mario Cazzola, this Review Series highlights 4 such genetic predisposition syndromes and provides strong support for the need to include germ line genetic testing for patients with myelodysplasia and myeloid leukemia.

Routine use of next-generation sequencing of hematologic malignancies has greatly expanded the representation of hereditary predisposition syndromes among patients with leukemia. Introduced by Associate Editor Mario Cazzola, this Review Series highlights 4 such genetic predisposition syndromes and provides strong support for the need to include germ line genetic testing for patients with myelodysplasia and myeloid leukemia.

Routine use of next-generation sequencing of hematologic malignancies has greatly expanded the representation of hereditary predisposition syndromes among patients with leukemia. Introduced by Associate Editor Mario Cazzola, this Review Series highlights 4 such genetic predisposition syndromes and provides strong support for the need to include germ line genetic testing for patients with myelodysplasia and myeloid leukemia.

Routine use of next-generation sequencing of hematologic malignancies has greatly expanded the representation of hereditary predisposition syndromes among patients with leukemia. Introduced by Associate Editor Mario Cazzola, this Review Series highlights 4 such genetic predisposition syndromes and provides strong support for the need to include germ line genetic testing for patients with myelodysplasia and myeloid leukemia.

CLINICAL TRIALS AND OBSERVATIONS

Ghosal hematodiaphyseal dysplasia (GHDD) is an extremely rare disorder associated with normocytic anemia and cortical bone thickening, caused by mutations in thromboxane A synthase 1 (TBXAS1). Marrow failure is thought to result from loss of thromboxane and a consequent increase in proinflammatory prostaglandin synthesis and is treated with corticosteroids. Brown and colleagues report on the treatment of 2 patients with nonsteroidal anti-inflammatory drugs, leading to cyclooxygenase inhibition and complete hematologic response, suggesting this should be first-line therapy for this rare disorder.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Over 95% of the population has been infected by Epstein-Barr virus, but why only some patients develop symptomatic infectious mononucleosis (IM) and why only a small subset of patients develop posttransplant lymphoproliferative disease (PTLD) after stem cell transplantation are unknown. Vietzen et al describe an interplay of genetic determinants in host and virus involving variants in host HLA-E that interact with specific latent membrane protein 1 peptide variants to modulate T-cell and natural killer cell responses that predict for IM and PTLD.

LYMPHOID NEOPLASIA

Translocation t(4;14) between the NSD2 gene and the immunoglobulin heavy-chain locus defines a high-risk subset of patients with newly diagnosed multiple myeloma (NDMM). Stong et al present a whole genome and transcriptome analysis of 258 t(4;14) patients compared to 183 non-t(4;14) patients with NDMM. The authors demonstrate that 3 different breakpoints within the NSD2 gene subdivide these patients prognostically, with only 1 subgroup demonstrating high risk, establishing a role for targeted sequencing in further defining prognosis.

Bruton tyrosine kinase (BTK) is a driver of chronic lymphocytic leukemia (CLL), and covalent inhibitors of BTK like ibrutinib have become central to CLL therapy. Resistance to ibrutinib is often associated with mutations that block binding. Zhang and colleagues report on excellent activity in patient-derived xenografts of a targeted protein degrader that links a noncovalent BTK-binding domain to cereblon, catalyzing ubiquitylation of BTK and targeting it for proteosomal degradation. Ongoing clinical studies may establish this as a strategy for overcoming BTK-inhibitor resistance.

MYELOID NEOPLASIA

Acute myeloid leukemia (AML) with erythroid or megakaryocytic differentiation (pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryocytic leukemia) has a poor response to therapy and a poor prognosis. Kuusanmäki and colleagues report on a high-throughput screen to identify potential drugs with improved efficacy. The authors show that these subtypes depend on BCL-XL and not on BCL2 or MCL; consequently, BCL-XL inhibition was effective in cell lines and primary cells that were resistant to venetoclax.

TRANSPLANTATION

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for hematologic malignancies, depending on a graft-versus-leukemia (GVL) effect; however, many patients go on to relapse. Karl et al investigated the role of reactive oxygen species (ROS) in abrogating GVL. The authors report elevated levels of 8-hydroxydeoxyguanosine, a biomarker of oxidant stress, in patients after allo-SCT. Continued high levels were associated with T-cell activation, markers of T-cell exhaustion, and shorter overall survival, highlighting ROS as an important contributor to relapse.

LETTER TO BLOOD

BLOOD WORK

ERRATA

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