Authors
Hannah C Beird, Sankaranarayanan Kannan, Jingjing Liu, Janice Chen, Arturo Olguin, Poonam Desai, Tianyu Cai, Lina Han, Jennifer L Cotton, Sandeep Singh, Saurabh Kumar Gupta, Latasha Little, Marcos R Estecio, Xingzhi Song, Hussein A Abbas, Jianhua Zhang, Curtis Gumbs, Christopher Brooks, Hagop Kantarjian, Michael Andreeff, Marina Konopleva, P Andrew Futreal, Naveen Pemmaraju
Published in
Leukemia. Jul 06, 2026. Epub Jul 06, 2026.
Abstract
Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.
PMID:
42410207
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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