Biology subjects

Enver, T.

Publications and source records attributed to Enver, T..

8 recordsLinked to original sources

bioRxiv2026

Dynamics of the B-Cell gene regulatory network in differentiation determine evolutionary trajectories of childhood leukaemogenesis

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most frequent paediatric malignancy. Despite extensive molecular and cellular characterization a mechanistic model of leukaemogenesis has not yet been developed. Here we present a multi-valued logical model of B-cell differentiation, centred on a core pentad of transcription factors whose dysregulation results in the developmental arrest characteristic of BCP-ALL. Whilst B-cell maturation follows a fixed and sequential differentiation process, leukaemic transformation is driven by stochastic genetic insults. Integrating BCR-ABL1 as the initiating event, we model alternative evolutionary trajectories by introducing secondary mutations at different time points within synchronous simulations. We demonstrate that the combination, order and timing of secondary mutations dictate maturation arrest points and fitness, explaining how different patterns of mutations seen in patients may arise and in turn influence disease severity. This platform provides a generalisable framework to model driver mutations in their developmental context to predict evolutionary trajectories in cancer.

cancer biology↗

bioRxiv2025

Targeting mitochondria mitigates chemotherapy-induced bone marrow dysfunction

Chemotherapy has revolutionized cancer treatment but its long-term impact on healthy tissues, particularly the rapidly dividing hematopoietic system, remains a significant concern. We show that the chemotherapeutic agent 5-fluorouracil (5-FU) causes significant long-term defects of the hematopoietic system that mimics ageing, including myeloid lineage skewing and hematopoietic stem cell (HSC) dysfunction. Importantly, chemotherapy exposed HSCs remain in an inflammatory state coupled with mitochondrial dysfunction, both of which are implicated in ageing and MDS development. Remarkably, five days of MitoQ treatment fully reversed 5-FU-induced myeloid skewing and caused significant recovery of HSC transcriptome and function in a stable manner. Thus, our results demonstrate that repeated chemotherapy induces long-term bone marrow dysfunction driven by metabolically unfit HSCs that can be pharmacologically rescued. This work opens up novel avenues to explore supportive treatment for patients undergoing any type of myelo-ablative chemotherapy. HighlightsO_LICommonly used chemotherapy drugs cause stable lineage-specific cytopenias despite recovery of total blood counts. C_LIO_LI5-FU-induced hematopoietic dysfunction phenocopies premature hematopoietic ageing. C_LIO_LIChemotherapy-induced changes stem from HSCs that are self-renewal competent but differentiation incompetent. C_LIO_LIMitochondrial-targeted treatment rescues 5-FU-induced myeloid bias through correction of HSC transcriptome and function. C_LI

cell biology↗

bioRxiv2023

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable. Since transcription factors like EVI1 are notoriously hard to target, insight into the mechanism by which EVI1 drives myeloid transformation could provide alternative avenues for therapy. Applying protein folding predictions combined with proteomics technologies, we demonstrate that interaction with CTBP1 and CTBP2 via a single PLDLS motif in EVI1 is indispensable for leukemic transformation. Furthermore, we show that a 4x PLDLS repeat construct outcompetes binding of EVI1 to CTBP1 and CTBP2 and thereby inhibits proliferation of 3q26/MECOM rearranged AML both in in vitro and in xenotransplant models. This proof-of-concept study opens the possibility to therapeutically target one of the most incurable forms of AML with specific EVI1-CTBP inhibitors. This has important implications for other tumour types with aberrant expression of EVI1 as well as for cancers transformed by distinct CTBP-dependent oncogenic transcription factors.

cancer biology↗

bioRxiv2022

Complex genotype-phenotype relationships shape the response to treatment of Down Syndrome Childhood Acute Lymphoblastic Leukaemia

Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this eco-system and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.

cancer biology↗

bioRxiv2020

Cell cycle corruption in a preleukemic ETV6-RUNX1 model exposes RUNX1 addiction as a therapeutic target in acute lymphoblastic leukemia

The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBF{beta} results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBF{beta}-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results implicate chemical intervention in the RUNX1 program as an exciting therapeutic opportunity in ALL.

cancer biology↗

bioRxiv2020

An instructive role for IL7RA in the development of human B-cell precursor leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is preceded by a clinically silent pre-leukemia. Experimental models that authentically re-capitulate disease initiation and progression in human cells are lacking. We previously described activating mutations in interleukin 7 receptor alpha (IL7RA) that are associated with the poor-prognosis Philadelphia-like (Ph-like) subtype of BCP-ALL. Whether IL7RA signaling has a role in initiation of human BCP-ALL is unknown. IL7RA is essential for mouse B-cell development; however, patients with truncating IL7RA germline mutations develop normal mature B-cell populations. Herein, we explore the consequences of aberrant IL7RA signaling activation in human hematopoietic progenitors on malignant B-cell development. Transplantation of human cord-blood hematopoietic progenitors transduced with activated mutant IL7RA into NOD/LtSz-scid IL2R{gamma}null mice resulted in B-cell differentiation arrest with aberrant expression of CD34+ and persistence of pro-B cells that survive despite failing to achieve productive rearrangement of immunoglobulin V(D)J gene segments. Activation of IL7RA signaling enhanced self-renewal and facilitated the development of a BCP-ALL in secondary transplanted mice. The development of leukemia was associated with spontaneous acquired deletions in CDKN2A/B and IKZF1 similar to what is observed in Ph-like BCP-ALL in humans. Single cell gene expression analysis suggested that pre-leukemic cells resided within a subpopulation of early B-cell precursors with CD34+CD10highCD19low immunophenotype. The development of a bona fide BCP-ALL from IL7RA transduced cells supports the hypothesis that aberrant activation of the IL7RA pathway in human B-cell lineage progenitors has an instructive role by creating a pre-leukemic state which is vulnerable to transformation. These are the first demonstrations of a role for IL7RA in human B-cell differentiation and of a de-novo Ph-like BCP-ALL development from normal human hematopoietic progenitors in vivo.

cancer biology↗

bioRxiv2019

Generation and Trapping of a Mesoderm Biased State of Human Pluripotency

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explored mesoderm lineage-bias within the human pluripotent stem cell compartment. We identified a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programs. Functionally these cells could initiate stem cell cultures and exhibited mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we could trap and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of cross-antagonistic signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.

cell biology↗

bioRxiv2017

Challenges And Emerging Directions In Single-Cell Analysis

Single-cell analysis is a rapidly evolving approach to characterize genome-scale molecular information at the individual cell level. Development of single-cell technologies and computational methods has enabled systematic investigation of cellular heterogeneity in a wide range of tissues and cell populations, yielding fresh insights into the composition, dynamics, and regulatory mechanisms of cell states in development and disease. Despite substantial advances, significant challenges remain in the analysis, integration, and interpretation of single-cell omics data. Here, we discuss the state of the field and recent advances, and look to future opportunities.

genomics↗