Table of Contents
HOW I TREAT
In this How I Treat article, Rubnitz and Kaspers offer their views on management of pediatric AML. Using 4 cases representing recurring challenging scenarios, they highlight pertinent evidence, key gaps in knowledge, and points of contention. Representing perspectives from centers in North America and Europe, the authors offer practical suggestions for decision-making in these difficult situations.
IMMUNOBIOLOGY AND IMMUNOTHERAPY
SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation
Clinical Trials & Observations
SASH3 is an intracellular adaptor protein that is expressed mainly in lymphocytes and is important for proliferation, activation, and survival of T cells. Delmonte and colleagues describe a novel human X-linked immunodeficiency due to hemizygous loss-of-function variants of SASH3. Patients with this immunodeficiency have abnormalities in T cells as well as immune dysregulation manifesting as recurrent infections and refractory autoimmune cytopenias.
JAK inhibition for murine HLH requires complete blockade of IFN-γ signaling and is limited by toxicity of JAK2 inhibition
In this Brief Report, Chaturvedi et al explore how JAK inhibitors may be applied in the hyperinflammatory disorder hemophagocytic lymphohistiocytosis (HLH), using a murine model. They reveal that JAK inhibition results in intermittent blockade of interferon γ (IFN-γ), the cytokine central to HLH pathobiology. Coinhibition of JAK1 and IFN-γ improves HLH control but not survival compared to anti–IFN-γ blockade alone, while addition of ruxolitinib to anti–IFN-γ worsens survival due to toxicity. Clinical trial data with ruxolitinib are needed to understand its potential role in this condition.
T-cell acute lymphoblastic leukemia (T-ALL) is often not cured by frontline chemotherapy, and efforts to improve treatment by targeting oncogenes such as NOTCH1 have been hampered by toxicity. Silva and colleagues studied primary patient samples to show that high-level interleukin 7 receptor α (IL7Rα) gene expression correlates with ongoing, oncogenic IL7R-mediated signaling. Using new in vivo models, they characterized the impact of IL7Rα expression on the pathogenesis of T-ALL and its response to various targeted therapies that reduce IL7-related signaling.
B-cell receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter transformation
Transformation to large cell lymphoma (Richter syndrome) in 2% to 10% of patients with chronic lymphocytic leukemia (CLL) carries a very poor prognosis, but its pathobiology is notoriously hard to study using primary samples and in vitro models. Chakraborty et al used murine models and CRISPR technology to demonstrate how biallelic loss of function of TP53 and the cell cycle regulators CDKN2A and CDKN2B facilitates dysregulated B-cell receptor (BCR)–dependent proliferation while creating vulnerabilities to therapeutic targeting with a combination of BCR and CDK4/6 inhibitors.
CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues
Yu and colleagues report new insights into how interaction between acute myeloid leukemia (AML) cells and the bone marrow niche influences sensitivity of AML to venetoclax. Using primary patient cells and murine and zebrafish models, they found that 2 microenvironmental ligands (CD44 and CXCL12) collaborate to stimulate CXCR4-mediated signaling pathways in AML cells, leading to increased stem cell features, decreased apoptosis, and reduced sensitivity to venetoclax. Targeting this microenvironmental mechanism of resistance may augment venetoclax activity in AML.
LETTER TO BLOOD
CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel
Clinical Trials & Observations
Split-Venus bimolecular fluorescence complementation (BiFC) shows a direct interaction between CD44 (CD44s-VC) and CXCR4 (CXCR4-VN) at the membrane upon induction with CXCL12. The BiFC signal (yellow) is detected at the membrane. The nuclei are stained with DAPI (4′,6-diamidino-2-phenylindole; blue). See the article by Yu et al on page 1069.
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