Telliam Dushime, G. | Search bioRxiv

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↗

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↗