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. 2025 May 2;15(1):83.
doi: 10.1038/s41408-025-01284-y.

CD56 expression modulates NAD+ metabolic landscape and predicts sensitivity to anti-CD38 therapies in multiple myeloma

Giulia Giorgetti  1   2   3 , Elena Maroto-Martin  3 , Debora Soncini  1 , Daniela Fenoglio  2   4 , Pamela Becherini  1   2 , Andrea Benzi  5 , Silvia Ravera  2   5 , Isabella Traverso  1 , Francesco Ladisa  1   2   3 , Francesco Lai  2 , Giulia Rivoli  6 , Dario Truffelli  1 , Aimable Nahimana  7 , Antonia Cagnetta  1   2 , Fabio Guolo  1   2 , Chiara R M Uras  3 , Anaïs Schavgoulidze  3   8 , Jessica Fong Ng  3   9 , Alessio Nencioni  2   10 , Santina Bruzzone  2   5 , Nikhil C Munshi  3   11 , Roberto Massimo Lemoli  1   2 , Mariateresa Fulciniti  3   11 , Michele Cea  12   13
Affiliations

CD56 expression modulates NAD+ metabolic landscape and predicts sensitivity to anti-CD38 therapies in multiple myeloma

Giulia Giorgetti et al. Blood Cancer J. .
No abstract available

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. CD56 levels on bone marrow plasma cells enhance anti-MM activity of NAD+-depleting agents by affecting CD38 enzymatic activity.
A MM1S, RPMI 8226, and U266 cells infected with CD56 expression lentiviral plasmid (CD56 OE), or empty vector, were assayed for their CD38 enzymatic activity (GDP-ribosyl cyclase) and intracellular NAD+ content. Data are presented as mean ± S.D. (n = 3) (*p < 0.05, **p < 0.01; ***p = 0.0003; ****p < 0.0001; unpaired t test). B, C Cell lysates from control and CD56 OE (B) and KD (C) MM cells were subjected to WB analysis using the indicated Abs and GAPDH as loading control. One representative blot of at least two independent experiments performed is shown. D MM1S cells ectopically overexpressing CD56 (pLV CD56 OE) or empty vector (pLV CTR) were treated with increasing doses of FK866 (0–2 nM), OT-82(0–30 nM), STF118804 (0–30 nM), GNE-617 (0–30 nM) and CHS-828 (0–30 nM) for 96 h. Cell viability was measured with MTS assay and presented as a percentage of cell viability from untreated cells. Data are presented as mean ± S.D (n = 3) (*0.05 < p ≤ 0.005, **0.005 < p ≤ 0.001, ***0.0009 ≤ p ≤ 0.0007; unpaired t test). E MM1S cells infected with a lentiviral plasmid carrying short hairpin RNA targeting CD38 (shRNA#3) or a scramble control were assayed for CD38 mRNA expression. F CD38-silenced cells were subsequently infected with lentiviral plasmids either overexpressing (OE) or downregulating (KD) CD56 levels. G Finally, intracellular NAD+ levels in these cells were measured and expressed as nmol/mg. Data in (E–G) are presented as mean ± SD; *p = 0.02; **0.019 ≤ p ≤ 0.003; ***p = 0.0002; ****p < 0.0001 (unpaired t test).
Fig. 2
Fig. 2. CD56 levels in MM patients predict outcome following metabolism-targeting agents.
A Heatmap showing FK866 activity signature expression in MM patients derived from the MMRF_CoMMpass_IA18_salmon_geneUnstranded_tpm.tsv dataset grouped by GSVA method as “FK866 sensitive” (patients with gene expression in accordance with FK866 treatment) and “FK866 resistant” (patients with non-overlapping profiles). B Number of MM patients from CoMMpass study exhibiting an FK866-sensitive signature, separated according to CD56 expression levels: high vs. low (N = 118 vs. 175; p value = 0.001; exact binomial test). C Kaplan–Meyer curves of the progression-free survival probability for FK866-sensitive patients based on their CD56 expression level (p = 0.024; Peto-Peto test). D Bar graph showing the percentage of indicated chromosomal abnormalities in MM patients included in MMRF CoMMpass, according to their CD56 expression levels (high vs. low). SRCA indicates standard risk, and HRCA indicates patients with ≥2 CA. E CD38 enzymatic activity (GDP-ribosyl cyclase) and intracellular NAD+ content in MM1S CD56-overexpressing cells compared to control cells at baseline and after treatment with indicated 1 µg/mL of anti-CD38 MoAbs for 12 h. Data are presented as mean ± S.D. (n = 3). (ns not significant, *p < 0.05; ***p < 0.001; ****p < 0.0001; unpaired t tes).
Fig. 3
Fig. 3. CD56 modulation in CD38 high-expressing cells modulates ADCC response to anti-CD38 Monoclonal Antibodies.
A H929 cells infected with CD56 expression lentiviral plasmid (CD56 OE) or empty vector. On the left, western blot analysis (WB) shows CD56 expression in H929 control cells (pLV CTR) and CD56 OE cells (pLV CD56 OE); GAPDH was used as loading control. On the right, cells were assayed for their CD38 enzymatic activity (GDP-ribosyl cyclase) and intracellular NAD+ content. Data are presented as mean ± S.D (n = 3) (*p < 0.05; unpaired t test). B On the left, western blot analysis (WB) shows CD38 expression in H929 control cells (pLV CTR) and CD38 high-expression cells (pLV hCD38); GAPDH was used as loading control. On the right, surface expression level of CD56 in H929 cells overexpressing CD38 (pLV hCD38) transduced with CD56 knockdown (CD56 pLV shRNA#2) or scramble control (pLV SCR). C ADCC assays were conducted using H929 CD38OE cells transduced with scramble control (pLV SCR) or shRNA targeting CD56 (pLV CD56 shRNA#2). Effector-to-Target (E:T) ratios were evaluated using NK cells from healthy donors, with treatment conditions including Daratumumab (DARA, 10 µg/mL) and Isatuximab (ISA, 10 µg/mL). D Progression-free survival (PFS) from the first day of Isa-based therapies (11 Isa-PD and 9 Isa-KD) in our cohort of RRMM patients exhibiting high (red) or low (blue) levels of CD56 on their bone marrow plasma cells. Log rank test; p = 0.046.
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References

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