Issue 4, Volume 128

Cover Figure: Extracellular vesicles released from CLL cells alter CD4+ T-cell function. See the article by Smallwood et al.

WASHINGTON, July 28, 2016 – Welcome to “This Week in Blood,” a weekly snapshot of the hottest studies from each week’s issue of Blood, the official journal of the American Society of Hematology (ASH), hand-picked by Blood Editor-in-Chief Bob Löwenberg, MD, PhD, and Deputy Editor Nancy Berliner, MD.

GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGFβRII heterodimer
Growth factor differentiation factor 15 (GDF-15) is a member of the transforming growth factor β (TGFβ) superfamily that has been previously demonstrated to inhibit integrin activation-dependent neutrophil recruitment to sites of inflammation. Artz and colleagues now demonstrate that GDF-15 exercises this effect by binding to a TGFβ receptor dimer and inhibiting integrin activation through inhibiting activation of the Rap-1 GTPase.

Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism
Hawke and colleagues studied three families with von Willebrand disease (VWD) caused by aberrant splicing leading to dysfunctional von Willebrand factor or degradation of abnormal protein. They observed that aberrant splicing is increased by shear stress on endothelial cells and that some aberrant splicing can occur in the absence of mutations in normal individuals. Since not all the studied mutations lie within canonical splice sites, they hypothesize that splicing mutations, thought to cause about 10% of VWD cases, are probably a more common cause of the disease than estimated.

IL-4 rescues surface IgM expression in chronic lymphocytic leukemia

Dual TORK/DNA-PK inhibition blocks critical signalling pathways in chronic lymphocytic leukemia
B-cell receptor (BCR) inhibition with ibrutinib or idelalisib has an important impact on chronic lymphocytic leukemia (CLL) therapy. Two papers in this issue report on aspects of BCR signaling. 

It is an unexplained paradox that although CLL cells are activated to proliferate via the BCR, circulating CLL cells express low levels of surface immunoglobulin (Ig) and respond poorly to antigen. In the first paper, Guo and colleagues describe results that may explain this apparent contradiction. They report that peripheral CLL cells have poor assembly of the BCR because of impaired CD79b expression but that CD79b expression is rescued by interleukin-4 (IL-4). Since IL-4 is highly expressed in CLL lymph nodes, this suggests that BCR expression is enhanced in lymph nodes where CLL cells proliferate in the presence of IL-4 and that this expression declines upon release into the circulation.

The weak signaling of the BCR may partly explain the limited ability of ibrutinib and idelalisib to induce cell death in CLL cells. Resistance to BCR inhibitors arises from mutations that target DNA damage response or BCR signaling pathways. In the second paper, Thijssen and colleagues report the effect of TORK/DNA-PK inhibition in CLL, demonstrating in vitro efficacy on cells from patients with resistance to fludarabine, venetoclax, and idelalisib and suggesting a potential novel therapy for resistant CLL.

How I treat acute myeloid leukemia presenting with preexisting comorbidities
Ofran and colleagues use a series of vignettes to illustrate their approach to treating acute myeloid leukemia in patients with comorbid disease, including ischemic cardiac disease, renal disease with and without dialysis, and liver disease and cirrhosis.

Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study
Bochtler and colleagues report the results of a long-term follow-up study of AL amyloidosis patients after high-dose melphalan and autologous stem cell transplantation, and they correlate outcomes with cytogenetic aberrations. The study confirms that long-term outcomes are good and that t(11;14) confers an improved overall and event-free survival.

This week's complete table of contents

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Blood (, the most cited peer-reviewed publication in the field of hematology, is available weekly in print and online. Blood is the official journal of the American Society of Hematology (ASH) (, the world’s largest professional society concerned with the causes and treatment of blood disorders.

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