The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.
Relapse of acute leukemia following hematopoietic stem cell transplantation (HSCT) usually represents return of an original disease clone, having evaded eradication by pretransplant chemo-/radiotherapy, conditioning, or posttransplant graft-versus-leukemia (GVL) effect. Rarely, acute leukemia can develop de novo in engrafted cells of donor origin. Donor cell leukemia (DCL) was first recognized in 1971, but for many years, the paucity of reported cases suggested it to be a rare phenomenon. However, in recent years, an upsurge in reported cases (in parallel with advances in molecular chimerism monitoring) suggest that it may be significantly more common than previously appreciated; emerging evidence suggests that DCL might represent up to 5% of all posttransplant leukemia "relapses." Recognition of DCL is important for several reasons. Donor-derivation of the leukemic clone has implications when selecting appropriate therapy, because seeking to enhance an allogeneic GVL effect would intuitively not have the same role as in standard recipient-derived relapses. There are also broader implications for donor selection and workup, particularly given the growing popularity of nonmyeloblative HSCT and corresponding rising age of the potential donor pool. Identification of DCL raises potential concerns over future health of the donor, posing ethical dilemmas regarding responsibilities toward donor notification (particularly in the context of cord blood transplantation). The entity of DCL is also of research interest, because it might provide a unique human model for studying the mechanisms of leukemogenesis in vivo. This review presents and collates all reported cases of DCL, and discusses the various strategies, controversies, and pitfalls when investigating origin of posttransplant relapse. Putative etiologic factors and mechanisms are proposed, and attempts made to address the difficult ethical questions posed by discovery of donor-derived malignancy within a HSCT recipient.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.