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Life sciences · Journal article
Blood · September 2, 2026
Raises a question worth testing. It does not answer one.
This mechanistic study uses multimodal profiling of primary T-ALL samples and preclinical models to characterize CD38 biology and propose two rational combinatorial strategies: CD38 + DFMO (polyamine disruption) and daratumumab + dasatinib (SRC kinase inhibition). The findings are exploratory and identify testable hypotheses rather than proven clinical interventions.
Multimodal mechanistic profiling (bulk RNA-seq, flow cytometry, CITE-seq, transcription factor CRISPR screen, metabolomic analysis) with preclinical validation. Pediatric T-cell acute lymphoblastic leukemia patients (primary tumors, cell lines, and patient-derived xenograft models). Clinical context: refractory or relapsed disease.. Intervention: CD38 perturbation (CRISPR, daratumumab); combination strategies: CD38 + difluoromethylornithine (DFMO); daratumumab + dasatinib. Compared with: Monotherapy (CD38 alone, daratumumab alone); untreated controls implied.
CD38 expression varies across genomic and immunophenotypic subtypes in 1,335 primary T-ALL tumors by bulk RNA sequencing. Broad surface CD38 expression confirmed in 150 primary samples by flow cytometry and 40 cases by CITE-sequencing. CRISPR transcription factor screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38.
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These findings propose rational combinatorial approaches (CD38 + DFMO, daratumumab + dasatinib) for potential future clinical testing in refractory/relapsed pediatric T-ALL, but the work is mechanistic and does not yet provide direct evidence of clinical benefit.
Multimodal mechanistic profiling identifying potential CD38-driven pathways and rational combinations in T-ALL, supported by preclinical models and transcriptomic associations, but lacking clinical outcome data.
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These findings propose rational combinatorial approaches (CD38 + DFMO, daratumumab + dasatinib) for potential future clinical testing in refractory/relapsed pediatric T-ALL, but the work is mechanistic and does not yet provide direct evidence of clinical benefit.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.
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