Issue Archive

In a study reported in a Plenary Paper, Huang et al used a CRISPR screen to identify ATF-4 as a critical species-specific protein regulating fetal hemoglobin. ATF-4 downregulates γ-globin through activating transcription of BCL11A, a silencer of the γ-globin gene locus.

In this Blood Spotlight, the authors discuss the clinical data supporting the use of lenalidomide alone and in combination with rituximab in the treatment of follicular lymphoma.

Wei and colleagues report the results of a randomized trial of low-dose cytarabine (LDAC) combined with venetoclax vs LDAC alone in elderly “unfit” patients with acute myeloid leukemia (AML), demonstrating that venetoclax increases complete remission rate and overall survival.

Immunomodulatory imide drugs (IMiDs) are important for the treatment of multiple myeloma and 5q− myelodysplasia, but thrombocytopenia can be a dose-limiting toxicity. Proplatelet formation is known to be dependent on estradiol signaling in the marrow. The authors demonstrated that IMiDs decrease proplatelet formation by promoting proteasomal degradation of aromatase, which is critical for estradiol biosynthesis.

Neurotrophic receptor tyrosine kinase (NTRK) gene mutations have been found and targeted in solid tumors. Joshi et al identified NTRK point mutations in myeloid neoplasms, all in association with other driver mutations. The functionally important mutations conferred responsiveness to NTRK inhibitors, indicating the potential importance of evaluating the full genomic landscape of secondary mutations in hematologic malignancies.

Megakaryoblastic leukemia 1 (MKL1) is a widely expressed transcription factor that is important for actin polymerization. Through study of 2 siblings with primary immunodeficiency due to MKL1 deficiency, the authors demonstrated a profound defect in neutrophil motility. Interestingly, fibroblasts had normal migratory properties, likely due to compensation with a closely related MKL2 protein that is not expressed in neutrophils.

Davids and colleagues present results of a clinical trial of PD-1 blockade for relapsed hematologic malignancies following allogeneic stem cell transplantation. They report modest antitumor activity and significant immune-related adverse events.

Lucas et al explored the clonal dynamics of chronic lymphocytic leukemia (CLL) patients following treatment and subsequent acquired resistance to ibrutinib and then venetoclax. They report different patterns of resistance mutations from previously reported changes following venetoclax treatment in the absence of prior BTK inhibitor therapy.