Biology subjects

Krzywon, A.

Publications and source records attributed to Krzywon, A..

3 recordsLinked to original sources

bioRxiv2025

DNMT3A-R882 mutations intrinsically drive dysfunctional neutropoiesis from human haematopoietic stem cells

Clonal haematopoiesis (CH) arises from the expansion of hematopoietic stem cells (HSCs) carrying leukaemia-associated somatic mutations. CH is linked to pathological immune dysregulation and a greater risk of age-related inflammatory diseases. Yet, how CH mutations impact HSC differentiation into immune effector cells remains understudied. Here, we report a single-cell resolution functional and multi-omic investigation of HSC clonal and differentiation dynamics in individuals with DNMT3A-R882 CH. DNMT3A-R882 reshapes the clonal architecture of haematopoiesis towards an aged phylogenetic structure. Functionally, DNMT3A-R882 HSCs produce decreased monocytic output but more abundant and mature neutrophil progeny compared to WT HSCs in the same individual. Whereas DNMT3A-R882 myeloid progenitors display attenuated inflammatory transcriptional programmes, DNMT3A- R882 mature neutrophils acquire proinflammatory and immunomodulatory features typical of maladaptive immunity and CH co-morbidities. Our findings, validated in humanised mice, identify aberrant DNMT3A-R882 HSC-driven neutropoiesis as a key link between CH, immune dysregulation and risk of inflammatory disease.

cell biology↗

bioRxiv2021

Heat Shock Factor 1 (HSF1) as a new tethering factor for ESR1 supporting its action in breast cancer.

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was recently linked to estrogen (E2) signaling through ESR1. We found that an HSF1 deficiency could lead to the inhibition of the mitogenic action of E2 in breast cancer cells. The stimulatory effect of E2 on the transcriptome is weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ESR1 to chromatin. HSF1 and ESR1 can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ESR1 through a mechanism involving chromatin reorganization. Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome diversity in ER-positive breast cancer and can enhance the genomic action of ESR1. Moreover, ESR1 and HSF1 are only prognostic when analyzed together (the worst prognosis for ER-/HSF1high cancers).

cancer biology↗

bioRxiv2019

A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a-CD7- subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.

cancer biology↗