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EDITORIAL

Edited by Associate Editor Mario Cazzola, this review series highlights 3 specific areas of scientific and clinical advances in understanding disorders of red cell production. Nobel laureate Gregg Semenza focuses on the hypoxia-inducible factor (HIF) pathway, from discovery through the understanding of its role in regulation of erythropoiesis to the potential of HIF inhibitors as therapy. In the second article, Caulier and Sankaran update the concepts of regulation of erythroid differentiation. Complementing these 2 articles, Cazzola provides a review on the clinical problem of ineffective erythropoiesis; this article highlights the interplay between inherited and acquired anemias due to ineffective erythropoiesis and iron-loading and the prospects for improved therapies.

BLOOD COMMENTARIES

PLENARY PAPER

DNA cross-link repair 1B (DCLRE1B), also known as Apollo, is a multifaceted protein that acts as a DNA exonuclease in DNA repair and a protector of telomeres during S phase. In this Plenary Paper, Kermasson et al report on the discovery of biallelic mutations of DCLRE1B in 3 unrelated children who presented with hematologic, immunologic, and mucocutaneous features suggestive of dyskeratosis congenita, but with unexpectedly normal telomere lengths. Their work establishes Apollo deficiency as a new bone marrow failure syndrome and extends our understanding of telomeropathies.

REVIEW SERIES

Edited by Associate Editor Mario Cazzola, this review series highlights 3 specific areas of scientific and clinical advances in understanding disorders of red cell production. Nobel laureate Gregg Semenza focuses on the hypoxia-inducible factor (HIF) pathway, from discovery through the understanding of its role in regulation of erythropoiesis to the potential of HIF inhibitors as therapy. In the second article, Caulier and Sankaran update the concepts of regulation of erythroid differentiation. Complementing these 2 articles, Cazzola provides a review on the clinical problem of ineffective erythropoiesis; this article highlights the interplay between inherited and acquired anemias due to ineffective erythropoiesis and iron-loading and the prospects for improved therapies.

Edited by Associate Editor Mario Cazzola, this review series highlights 3 specific areas of scientific and clinical advances in understanding disorders of red cell production. Nobel laureate Gregg Semenza focuses on the hypoxia-inducible factor (HIF) pathway, from discovery through the understanding of its role in regulation of erythropoiesis to the potential of HIF inhibitors as therapy. In the second article, Caulier and Sankaran update the concepts of regulation of erythroid differentiation. Complementing these 2 articles, Cazzola provides a review on the clinical problem of ineffective erythropoiesis; this article highlights the interplay between inherited and acquired anemias due to ineffective erythropoiesis and iron-loading and the prospects for improved therapies.

Edited by Associate Editor Mario Cazzola, this review series highlights 3 specific areas of scientific and clinical advances in understanding disorders of red cell production. Nobel laureate Gregg Semenza focuses on the hypoxia-inducible factor (HIF) pathway, from discovery through the understanding of its role in regulation of erythropoiesis to the potential of HIF inhibitors as therapy. In the second article, Caulier and Sankaran update the concepts of regulation of erythroid differentiation. Complementing these 2 articles, Cazzola provides a review on the clinical problem of ineffective erythropoiesis; this article highlights the interplay between inherited and acquired anemias due to ineffective erythropoiesis and iron-loading and the prospects for improved therapies.

IMMUNOBIOLOGY AND IMMUNOTHERAPY

Immunotherapy for multiple myeloma shows great promise, but the optimal target for antibody-based therapies is uncertain. Anderson and colleagues describe a novel strategy for prioritizing potential candidate targets using mass-spectrometry-based plasma membrane profiling. Their work identifies a new membrane-associated antigen, SEMA4A. Anti-SEMA4A antibodies conjugated to toxins, eradicated myeloma cells in vitro and in vivo, and may clinically have therapeutic potential.

LYMPHOID NEOPLASIA

New therapeutic modalities for T-cell acute lymphoblastic leukemia (T-ALL) are needed to improve outcomes. Using elegant mouse modeling and differential analysis of chromatin structure in hematopoietic progenitor cells, Antoszewski and colleagues demonstrate how the transcription factor Tcf1, encoded by the Notch target gene Tcf7, shapes chromatin architecture to facilitate initiation of Notch-induced T-ALL. Their data point to alternative targets to NOTCH1 in this disease.

In a large, multicenter retrospective analysis of IV methotrexate (MTX) during frontline treatment for diffuse large B-cell lymphoma (DLBCL), Wilson et al report that high dose intravenous MTX given at the end of treatment was as effective and less toxic for central nervous system (CNS) prophylaxis than MTX given during chemoimmunotherapy. Furthermore, the overall rate of CNS relapse in patients receiving CNS prophylaxis was similar to that in patients not receiving intensive prophylaxis. These data call into question the selection of patients for CNS prophylaxis with intravenous MTX.

PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

PLATELETS AND THROMBOPOIESIS

Using a mouse model of thrombotic thrombocytopenic purpura (TTP), Shao and colleagues show that the deletion of platelet CLEC-2 decreases pulmonary arterial thrombosis and the severity of thrombocytopenia. They also show that an integrin αaIIbβ3 antagonist, eptifibatide, or aspirin reduces pulmonary arterial thrombosis in the TTP mice. These data indicate that platelet CLEC-2 regulates GPIbα-mediated activation of integrin αIIbβ3 in TTP and may be pharmacologically manipulated for therapeutic benefit.

RED CELLS, IRON, AND ERYTHROPOIESIS

GATA1 is the master erythroid transcription factor, with inherited mutations linked to dyserythropoietic anemias such as Diamond-Blackfan anemia, and somatically acquired mutations linked to transient myeloproliferative disease in Down syndrome. Ludwig et al reveal that novel missense mutations in an intrinsically disordered region (IDR) in the carboxyl-terminal domain of GATA1 cause a rare form of X-linked inherited hemolytic anemia. In addition to explaining the molecular basis for this disease, the data shed light on the precise function of the IDR in target gene activation.

THROMBOSIS AND HEMOSTASIS

LETTERS TO BLOOD

BLOOD WORK

CONTINUING MEDICAL EDUCATION (CME) QUESTIONS

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