[24] Development of a novel Ikaros/Aiolos transcriptional signature and correlation with patient response in multiple myeloma patients treated with CELMoDs

Wed, 08 Apr 2026 00:00:00 +0000

Multiple myeloma (MM) is a neoplasm characterized by the clonal proliferation of malignant plasma cells in the bone marrow. CELMoD™ agents—including iberdomide (IBER) and mezigdomide (MEZI)—modulate Cereblon to induce the degradation of the hematologic transcription factors Ikaros (Ik) and Aiolos (Ai), exerting anti-proliferative and pro-apoptotic effects on MM cells. While Ik/Ai protein degradation can be semi-quantified by immunohistochemistry (IHC), clinical responses are not always correlated with IHC readouts, motivating a more quantitative genomic approach.

We performed CUT&RUN and ChIP-seq on the H929 MM cell line to map Ik binding targets genome-wide. By intersecting these targets with differential expression analysis (DESeq2) across multiple CELMoD treatments (LEN, POM, MEZI, IBER) at multiple timepoints, we compiled a high-confidence Ik regulon consisting of 115 up-regulated and 95 down-regulated target genes.

Gene Set Variation Analysis (GSVA) was then applied to this regulon to derive a sample-level Ik activity score. Key findings include:

On-treatment decrease: RNA-seq paired samples from MEZI-treated (N=7) and IBER-treated (N=41) patients showed significantly lower Ik activity scores at cycle 2 day 15 compared to screening.
Association with survival: Using an optimal cutpoint, greater on-treatment reduction in Ik activity score was significantly associated with longer progression-free survival (PFS) in IBER-treated patients.
Concordance with IHC: The RNA-seq based score showed significant agreement with IHC-based Ik degradation scores in a validation cohort (N=22), supporting its use as a complementary or standalone biomarker.

This work establishes a robust transcriptomic framework for monitoring Ik/Ai target engagement and predicting clinical outcomes in MM patients receiving CELMoD therapy.

[25] DISSECTING THE MOLECULAR BASIS OF POTENT HBF INDUCTION BY BMS-986470: A MECHANISTIC STUDY OF ZBTB7A/WIZ DUAL DEGRADATION

Thu, 11 Jun 2026 00:00:00 +0000

Sickle cell disease (SCD) remains a major global health burden with limited therapeutic options. Reactivation of fetal hemoglobin (HbF) is clinically validated to mitigate disease severity. BMS-986470 is a first-in-class, orally bioavailable cereblon E3 ligase modulator (CELMoD™) that selectively degrades ZBTB7A and WIZ—two transcriptional repressors of the γ-globin genes previously considered undruggable—resulting in robust HbF induction and an erythroid program shift from adult β-globin toward fetal γ-globin expression. BMS-986470 is currently under clinical investigation (NCT06481306).

Aims

We delineated the molecular mechanisms underlying BMS-986470–mediated HbF induction, with a focus on developing a better understanding of the contributions of ZBTB7A and WIZ degradation.

Results

Genome-wide CRISPR screen. To compare the HbF-repressing capacity of ZBTB7A and WIZ, we performed an unbiased, phenotypic, genome-wide CRISPR-Cas9 screen in HUDEP-2 cells. Differential sgRNA enrichment/depletion between HbF-high and HbF-low populations provided a quantitative readout per gene. The screen recovered established HbF repressors (ZBTB7A, BCL11A, ZNF410, WIZ, CHD4), validating the approach. Notably, ZBTB7A-targeting sgRNAs were more enriched in HbF-high cells than WIZ-targeting sgRNAs, indicating stronger repression by ZBTB7A. Intriguingly, HBB emerged as the top-ranked HbF repressor genome-wide, consistent with reports that HBB promoter disruption facilitates fetal globin reactivation.

CRISPR knockout lines. We generated single and dual knockouts (KOs) of ZBTB7A/WIZ in HUDEP-2 cells. Immunoblotting showed greater γ-globin (HBG1/2) induction in ZBTB7A KO versus WIZ KO cells. The double KO further increased HBG1/2 and HbF tetramers while reducing adult β-globin (HBB) compared with either single KO, supporting a dominant role for ZBTB7A in fetal globin silencing.

Chromatin architecture by Micro-C. BMS-986470 induced a pronounced looping switch—reduced LCR–HBB contacts and increased LCR–HBG contacts—at the β-globin locus. Micro-C in KO lines showed that both ZBTB7A and WIZ loss disrupt LCR–HBB contacts; however, ZBTB7A KO produced a substantially stronger gain in LCR–HBG looping than WIZ KO. These findings implicate ZBTB7A as the stronger mediator of LCR-driven promoter competition and explain why dual degradation by BMS-986470 leads to a robust adult-to-fetal globin chromatin and transcriptional switch.

Summary

We delineated the transcriptional and chromatin-level mechanisms of HbF regulation and established a functional hierarchy between ZBTB7A and WIZ. These findings provide mechanistic insights into the therapeutic potential of BMS-986470 for SCD treatment.

This work was presented at the European Hematology Association (EHA) Annual Congress 2026 in Stockholm, Sweden (June 2026).

Paper-Conference |

[24] Development of a novel Ikaros/Aiolos transcriptional signature and correlation with patient response in multiple myeloma patients treated with CELMoDs

[25] DISSECTING THE MOLECULAR BASIS OF POTENT HBF INDUCTION BY BMS-986470: A MECHANISTIC STUDY OF ZBTB7A/WIZ DUAL DEGRADATION

Aims

Results

Summary