Biology subjects

Fioretos, T.

Publications and source records attributed to Fioretos, T..

5 recordsLinked to original sources

bioRxiv2025

The 3D genome of pediatric B-cell precursor acute lymphoblastic leukemia

Whereas the molecular pathogenesis of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) has been studied extensively, its 3D chromatin landscape - of vast importance for gene regulation - remains poorly explored. Here, we applied Micro-C, a high-resolution variant of Hi-C, to 35 primary pediatric BCP ALL cases, spanning all major genetic subtypes. We present a complete view of the chromatin interaction landscape in childhood ALL, with resolutions reaching up to 5 kb in individual samples and 1 kb in the aggregated dataset. Somatic genetic aberrations - including fusion genes, aneuploidy, and structural variants - were found to profoundly reshape the 3D genome organization, impacting chromatin compartmentalization (A/B), topologically associating domain (TAD) architecture, and regulatory element positioning. Notably, chromosomal gains were associated with weakened TAD boundaries and widespread gene dysregulation. In addition, our analysis identified over 25,000 chromatin loops anchored at regulatory elements--e.g., enhancer-promoter loops--regulating the expression of more than 10,000 protein-coding genes. Among these, we highlight regulatory loops that drive gene expression differences between BCP ALL subtypes in the absence of concurrent somatic genetic aberrations, including the known driver genes HOXA9, FLT3, TP53, CD44, IKZF1, ERG, and XBP1. Taken together, our study gives unprecedented insights into chromatin organization and gene regulation in the leukemogenesis of BCP ALL.

cancer biology↗

bioRxiv2025

The cellular state space of AML unveils novel NPM1 subtypes with distinct clinical outcomes and immune evasion properties

Acute myeloid leukemia (AML) is a genetically and cellularly heterogeneous disease. We characterized 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identified four main clusters, thereby extending current genomic classification of AML. Notably, NPM1 mutated AML could be stratified into two novel, clinically relevant classes, with NPM1class I associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation (HSCT). NPM1class II was instead associated with resistance to allogeneic T cells in an ex vivo co culture assay, and importantly, dismal survival following HSCT. These findings provide new insights into the cellular state space of AML, define new diagnostic entities, and highlight potential therapeutic intervention points. Key PointsO_LIThe bulk transcriptional profiles of AML are mainly driven by a diverse set of cellular signatures. C_LIO_LISingle cell RNA-sequencing of the most common AML subtypes reveals marked heterogeneity extending beyond current genomic classification schemes. C_LIO_LINPM1-mutated AML can be divided into two new classes, with distinct immune evasion mechanisms and survival after transplantation. C_LI

cancer biology↗

bioRxiv2024

NK cells control the progression of myelodysplastic syndrome but become initial disease target in NUP98-HOXD13 mouse model

Studies in NUP98/HOXD13 mouse model (NHD13tg), progressing from myelodysplastic syndrome (MDS) to different forms of leukemia, demonstrated that T cells had a limited anti-leukemia effect, suggesting the involvement of other immune cells. Natural killer (NK) cells control viral infection and cancer. In MDS and acute myeloid leukemia (AML), patients often acquire disease-induced NK cell dysfunctions. Here, we report that NK cells from NHD13tg mice were reduced before the MDS-onset and specific NK cell depletion accelerated the disease progression and severity. NK cells from NHD13tg mice showed perturbed differentiation and impaired IL-15/IL-2 responses. These defects were cell-intrinsic and mainly affected the KLRG1+ mature NK cells. The expression of Nfil3, Klf2 and Id2 genes, crucial for NK cell development, homeostasis and IL-15 responsiveness, was altered in immature NK cells from NHD13tg mice. Interestingly, these genes were changed in MDS and AML bone marrow patient-samples compared to healthy donors. Our findings highlight a critical role for NK cells in controlling MDS progression and identify new genetic markers for MDS and AML.

immunology↗

bioRxiv2024

Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. We have developed a humanized monoclonal antibody (mAb), DUNP19, that specifically binds to a phylogenetically conserved LRRC15 epitope and is internalized by target-expressing cancer and stromal cells. In xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]-DUNP19) enables non-invasive imaging and precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts (CAFs), halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a transforming growth factor beta (TGF{beta})-driven and LRRC15+ signature associated with immunotherapy resistance. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and aggressive disease. SIGNIFICANCEWe introduce a pioneering LRRC15-guided radio-theranostic approach integrating clinical imaging and radioimmunotherapy. Our strategy utilizes a mAb, DUNP19, to target LRRC15-expressing cancer cells and fibroblasts, demonstrating significant tumor reduction, prolonged survival, and reversal of TGF{beta}-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers.

pharmacology and toxicology↗

bioRxiv2022

Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring STAG2 mutations

Targeted therapies exploiting selective vulnerabilities of malignant cells are highly desired for clinical applications. The cohesin protein complex comprises of RAD21, SMC3, SMC1A as well as a fourth subunit that consists of either STAG1 or STAG2 and is essential for proper chromosomal segregation during mitosis. STAG2 loss-of-function mutations are recurrent driver events in acute myeloid leukemia (AML) and appear relatively early during leukemogenesis. Studies in cell lines have shown that STAG2 deficient cells are uniquely vulnerable to STAG1 perturbation, and this vulnerability could thus be exploited to selectively eliminate STAG2 null AML cells. Here we show that partial perturbation of STAG1 is well tolerated by normal human hematopoietic stem cells and does not affect their functionality. By contrast, STAG1 knockdown is lethal to STAG2 null human HSCs by inducing major mitotic defects. Moreover, STAG1 knockdown induced synthetic lethality in primary human AML cells harboring a STAG2 mutation and completely abrogated leukemia progression in xenograft models. Overall, our study provides proof-of-concept demonstration of a synthetic lethal approach to selectively target primary human cancer cells with STAG2 mutations

cancer biology↗