In This Issue

See article, p. 146.

CAR T cell (CART) therapy elicits clinical response in the majority of patients with multiple myeloma, but is often followed by a relapse. Loss of the CAR-targeted antigen expression by cancer cells is common at relapse and is considered among the main mechanisms limiting durability of response. Here Fernández de Larrea and colleagues develop approaches for simultaneously targeting BCMA and GPRC5D myeloma antigens by a single CART infusion. They demonstrate that BCMA/GPRC5D dual-specific CARTs eliminate myeloma cells positive for both antigens and protect mice from rechallenge with BCMA-negative myeloma cells. CART performance was best when BCMA/GPRC5D was introduced as a single bicistronic vector, as compared to pooled CARTs individually transduced with BCMA and GPRC5D, and with a vector encoding a bivalent CAR. If reproduced with other CARs, these findings suggest that bicistronic vectors are an optimal strategy to dual CART manufacture. It remains to be tested in a clinical setting whether BCMA/GPRC5D CAR T would prevent antigen escape and offer more durable remission than current mono-specific CARTs.

See article, p. 155.

Mediastinal gray zone lymphoma (MGZL) is a rare cancer with features intermediate between classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBL). More information on molecular and histopathological characteristics of MGZL is essential for clarifying diagnostic criteria and understanding its pathogenesis and responsiveness to therapies. Here Pittaluga and colleagues compare transcriptomic and histological patterns in a cohort of 20 MGZL, 18 cHL and 17 PMBL patients. The results further document intermediate and heterogeneous molecular phenotypes of MGZL and highlight features of potential relevance to diagnostics and therapy.

See article, p. 162.

Schmidt et al. elucidate the structural basis of AF9 binding to AF4, DOT1L, BCOR, and CBX8, revealing their mutually exclusive interactions. By structure-guided mutagenesis, the authors create a series of point mutants of AF9 and its partners, selectively abrogating either BCOR or CBX8 interactions. Disrupting the interaction with CBX8 impairs MLL-AF9 effect on proliferation but not leukemic potential. In contrast, a mutation that disrupts BCOR-binding also diminishes MLL-AF9 leukemogenic potential. Cells transduced with this mutant display low expression of EYA1 phosphatase and Myc signature genes, as well as low Myc protein level, as compared to unmodified MLL-AF9. Eya1 overexpression can partially restore Myc-dependent transcription and leukemic potential of the MLL-AF9 mutant, connecting Eya1 known role in promoting c-Myc protein stability to AF9-MLL pathogenesis. The findings establish AF9-BCOR-Eya1-Myc axis as a major contributor to MLL-AF9-driven leukemogenesis and highlight Eya1 as a potential therapeutic target in this disease.

See article, p. 178.

Notch hyperactivation is common in T-cell acute lymphoblastic leukemia (T-ALL). As Notch also plays essential roles in homeostasis of other tissues, toxicities of Notch inhibitors limiting their clinical use. Here McCarter and colleagues identify Ets1 transcription factor as a major coregulator of Notch transcription in T cells. Ets1 deficiency impedes normal T-cell development as well as Notch-mediated T-ALL. Ets1- and Notch-dependent genes show a large degree of overlap, including key oncogenic pathway components. Ets1 co-occupies most of Notch/RBPJ-bound genomic regions. H3K27ac deposition and binding to gene regulatory regions is impaired in the absence of Ets1, suggesting Ets1 may facilitate Notch transcriptional complex recruitment. Ets1 inhibition in Notch-induced transplanted model of T-ALL extend mouse survival and cooperates with low-dose Notch pharmacological blockade. At the same time, acute whole-body deletion of Ets1 gene causes less intestinal toxicity as compared to Notch inhibitor, raising hope that systemic Ets1 inhibition may have better safety profile as a T-ALL therapy.

See article, p. 198.

APOC2 is a constituent of lipoproteins carrying lipids in circulation. It can interact with CD36, which mediates intracellular fatty acid uptake. In this report, Zhang et al. identify APOC2 as a gene associated with MLL rearrangements and poor outcome in AML. Noting that APOC2 expression is elevated in AML cells, the authors interrogate its cell-autonomous role in leukemic cells. Gain-of-function and loss-of-function experiments reveal that APOC2 levels define AML cell growth rate in culture through CD36-dependent effects on metabolism and survival. Abrogating the APOC2-CD36 axis in vivo by CD36 blocking antibody or by inducible APOC2 shRNA delays leukemia progression in a mouse xenograft model. These findings expand the current understanding of lipid metabolism fueling leukemic cell growth and identify APOC2 and CD36 as potential therapeutic targets in AML.

In This Issue is written by Blood Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details.