Biology subjects

Lambo, S.

Publications and source records attributed to Lambo, S..

4 recordsLinked to original sources

bioRxiv2025

Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents

Cancer-directed drugs are often clinically deployed without definitive understanding of their molecular mechanisms of action (MOA). Hypomethylating agents (HMAs), which result in the degradation of the DNA methyltransferase 1 (DNMT1), have been deployed for decades in the treatment of haematological malignancies1,2. The precise mechanism of action of these drugs, however, has been debated, rendering the design of rational combination therapies challenging. Here, we identified the deubiquitinating enzyme USP48 as a crucial regulator of posttranslational histone modification in the context of DNA demethylation. USP48 loss selectively enhances response to DNMT1 inhibition, leading to a rapid induction of cell death. We demonstrate that USP48 is localized at sites of DNA damage and deubiquitinates H2A variants and proteins important for DNA damage repair. Functionally, loss of USP48 triggers an increase in chromatin accessibility upon HMA treatment, rendering AML cells more susceptible to DNA damage. Our results support USP48 as a posttranslational histone modifier for chromatin stability and DNA damage in response to HMA-related DNA demethylation. These findings propose USP48 as a new target for combination therapy with HMAs for acute myeloid leukaemia (AML).

cancer biology↗

bioRxiv2025

Bone marrow lymphocyte dynamics during chemotherapy in pediatric acute myeloid leukemia

A better understanding of lymphocyte dynamics during current treatment regimens in pediatric AML is urgently needed to understand whether the application of bispecific T-cell-engagers (BiTEs) during periods of low tumor burden could be a viable treatment strategy. In this study, we found that induction 1, comprising mitoxantrone-etoposide-cytarabine in nearly all patients (as part of the NOPHO-DBH AML-2012 protocol), led to preserved or increased relative lymphocyte abundances alongside marked blast reduction in most cases. This was accompanied by a shift towards higher T-cell fractions, potentially creating a favorable window for BiTE therapy. The absence of a correlation between blast reduction and lymphocyte changes suggests that chemotherapy exerts differential effects on the lymphocyte compartment. Despite the heterogeneity of agents used in induction 2, more than half of patients showed a decline in lymphocyte levels. Nonetheless, the increase in T- and B-cells observed in most patients from the NOPHO-AML 2004 cohort after induction 2 suggests that lymphocyte recovery at this treatment stage is not uniformly impaired. Our transcriptomic and ex vivo functional data align with preclinical findings in adult AML and provide a basis for further investigations in in vivo models and early clinical trials. Such efforts should prioritize novel BiTE constructs targeting multiple tumor-associated (e.g., NCT05673057) or tumor-specific antigens.

cancer biology↗

bioRxiv2024

CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias

Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing pro-differentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA, is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo, suggesting a broadly applicable differentiation-based approach for improving therapy.

cancer biology↗

bioRxiv2022

Transcriptional immunogenomic analysis reveals distinct immunological clusters in pediatric nervous system tumours

To inform immunotherapy approaches in children, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naive pediatric nervous system tumours (pedNST) spanning 12 cancer types from three public data sets. Within pedNST, we uncovered four broad immune clusters: Pediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Excluded (17%). We validated these clusters using immunohistochemistry, methylation immune inference, and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune-cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.

genomics↗