Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Cohen, Sandra; Bambace, Nadia M.; Ahmad, Imran; Burns, Linda J.; Roy, Jean; Lachance, Silvy; Bernard, Léa; Delisle, Jean-Sébastien; Roy, Denis‐Claude; Kiss, Thomas; Veilleux, Olivier; Zhang, Mei‐Jie; Tang, Xiaoying; Sauvageau, Guy

doi:10.1182/blood-2022-160417

Cited by 4 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[29][30][31] As an example, a recent retrospective study demonstrated lower NRM with UM171expanded CBT in comparison to CBT or HLA-matched unrelated transplantation. 32 There are limitations in the current study, including the lack of data on cell dose, HLA-matching, molecular risk and MRD positivity at transplantation for many patients, precluding the inclusion of these criteria in the multivariable models. Another limitation linked to the registry nature of this study is that we cannot exclude that the decision to use CBT differed between de novo and sAML.…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, recent advances in ex vivo cord blood expansion are also likely to reduce NRM not only by prompting engraftment and immune reconstitution but also by allowing the selection of HLA‐matched unit 29‐31 . As an example, a recent retrospective study demonstrated lower NRM with UM171‐expanded CBT in comparison to CBT or HLA‐matched unrelated transplantation 32 …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Baron,

Nagler,

Galimard

et al. 2023

Br J Haematol

View full text Add to dashboard Cite

SummaryWe investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T‐cell depletion and no post‐transplant cyclophosphamide. The primary end‐point of the study was leukaemia‐free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non‐significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non‐relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non‐significantly different LFS following CBT in adult patients with secondary versus de novo AML.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Baron,

Nagler,

Galimard

et al. 2023

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…To evaluate the impact of expanded CB on prognosis, a retrospective comparison was conducted between the results of clinical trials utilizing UM171-expanded CB and outcomes using non-manipulated CB and matched unrelated donor (MUD) transplantation 33 . The results revealed that the UM171 group exhibited lower NRM compared to the CB control group, along with improved 2-year graft-versus-host disease-free relapse-free survival (GRFS) and 1-year OS.…”

Section: Clinical Applicationsmentioning

confidence: 99%

Recent advances in ex vivo expansion of human hematopoietic stem cells

2023

BCT

View full text Add to dashboard Cite

Hematopoietic stem cells (HSCs) are a rare cell population present in the bone marrow. They possess self-renewal and multipotent differentiation capacities and play a crucial role in lifelong hematopoiesis and reconstitution of the hematopoietic system after hematopoietic stem cell transplantation (HSCT). HSCT remains the only curative treatment for refractory hematologic disorders. Umbilical cord blood (CB) has several advantages as an alternative donor for HSCT, including HLA flexibility and lack of donor burden. However, CB has limitations in terms of cell dose, restricted donor options, and prolonged time to engraftment. Development of techniques for expanding HSCs ex vivo , especially those contained in CB, has become a goal in the field of hematology. Attempts have been made to use various combinations of cytokines for this purpose, but these protocols showed limited expansion rates and did not progress to clinical applications. Recent advances that include the addition of small molecules to cytokines have enabled long-term and stable ex vivo expansion of human HSCs. Clinical trials have been conducted with HSCs expanded in CB using these techniques, confirming their efficacy and safety. Furthermore, we recently developed a recombinant cytokine-free, albumin-free culture system for long-term expansion of human HSCs. This approach has the potential to selectively expand human HSCs more effectively than the previous protocols. We herein present an overview of ex vivo culture protocols for expanding human HSCs together with the results of clinical trials that utilized these techniques.

show abstract

“…Small molecule agonists that promote the self-renewal and expansion of HSCs are important reagents for basic research and have clinical applications for cell-based therapies 15,16 . UM171 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

Yeo,

Zhang,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1 to promote the degradation of select HDAC1/2 corepressor complexes. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy (cryo-EM) analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an unexpected asymmetric assembly, in which a single UM171 molecule enables a pair of KBTBD4 KELCH-repeat propeller domains to recruit HDAC1 by clamping on its catalytic domain. One of the KBTBD4 propellers partially masks the rim of the HDAC1 active site pocket, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a separate and distinct interface. The overall neomorphic interaction is further buttressed by an endogenous cofactor of HDAC1-CoREST, inositol hexakisphosphate, which makes direct contacts with KBTBD4 and acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces defined by cryo-EM is demonstrated by in situ base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, our results reveal how the cooperativity offered by a large dimeric CRL E3 family can be leveraged by a small molecule degrader and establish for the first time a dual molecular glue paradigm.

show abstract

Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Cited by 4 publications

References 0 publications

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Recent advances in ex vivo expansion of human hematopoietic stem cells

Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

Contact Info

Product

Resources

About

Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Cited by 4 publications

References 0 publications

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study

Recent advances in ex vivo expansion of human hematopoietic stem cells

Asymmetric Engagement of Dimeric CRL3KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

Contact Info

Product

Resources

About

Asymmetric Engagement of Dimeric CRL3^KBTBD4by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes