Biology subjects

Gillis, N.

Publications and source records attributed to Gillis, N..

4 recordsLinked to original sources

bioRxiv2025

Cell state transitions drive the evolution of disease progression in B-lymphoblastic leukemia

Cancer stem cells (CSCs) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. CSCs reside in the CD34+/CD38- immunophenotypic subpopulation of acute myeloid leukemia (AML); correspondingly, the size of this subpopulation has a strong negative impact on overall survival. Isolation of CSCs from B-lymphoblastic leukemia (B-ALL) has proven difficult, and the cells of interest apparently are not isolated to the CD34+/CD38- compartment. This may be explained, in part, by temporal variations of CD34 and CD38 expression which result in stochastic cell state transitions (e.g., from CD34+/CD38+ to CD34+/CD38-). We present a mathematical model of these transitions and correlate salient findings with BCR::ABL1 status, minimal residual disease (MRD), and relapse in adult B-ALL. As the CSC hypothesis is well supported in AML, we focus on transitions to and from the hematopoietic stem cell compartment (CD34+/CD38-), which our findings suggest can be estimated from peripheral blood or bone marrow samples. Additionally, we find that BCR::ABL1 positive patient samples are associated with high transition rates into the CD34+/CD38- compartment, including self-renewal. In contrast, BCR::ABL1 negative patient samples have low CD34+/CD38- self-renewal rates and either high CD34+/CD38+ or CD34-/CD38+ incoming rates. High CD34+/CD38- self renewal is also associated with MRD post-induction chemotherapy. We find a lack of observable changes in cell state transitions between diagnosis and relapse specimens. Our analysis provide evidence of de-differentiation transitions to a CD34+/CD38-stem cell-like immunophenotype in leukemia samples collected from B-ALL patients, and the tendency for these transitions is especially strong for B-ALL with BCR::ABL1. The modeling framework used here is a novel, useful tool to infer both prognosis and genotype from routine flow cytometry data. Significance StatementFlow cytometry characterization of B-lymphoblastic leukemia samples (diagnosis, remission, relapse) is used to parameterize a mathematical model of cell state transition rates and stratify patients at risk for post-induction chemotherapy minimal residual disease.

cancer biology↗

bioRxiv2021

Clonal hematopoiesis is associated with increased toxicity in large B-cell lymphoma patients treated with chimeric antigen receptor T cell therapy

To explore the role of clonal hematopoiesis (CH) on chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep-sequencing on 114 large B-cell lymphoma patients treated with anti-CD19 CAR T-cells. We detected CH in 42 (36.8%) pre-treatment patient samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. The incidence of grade [≥]3 immune-effector cell-associated neurotoxicity syndrome (ICANS) was higher in CH-positive patients compared to CH-negative patients (45.2% vs. 25.0%, p=0.038). Higher toxicities with CH were primarily driven by three CH genes, DNMT3A, TET2 and ASXL1 (DTA mutations). The incidence of grade [≥]3 ICANS [58.9% vs. 25%, p=0.02] and grade [≥]3 cytokine release syndrome [17.7% vs. 4.2%, p=0.08] were higher in patients with DTA mutations than those without CH. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR-T therapy was higher in patients with CH than those without CH (19% [95%CI: 5.5-38.7] vs. 4.2% [95%CI: 0.3-18.4], p=0.028). Statement of SignificanceOur study reveals that clonal hematopoiesis mutations, especially those associated with inflammation (DNMT3A, TET2, ASXL1), are associated with severe grade toxicities in lymphoma patients receiving anti-CD19 chimeric antigen receptor therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted.

genetics↗

bioRxiv2020

Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TR{beta}) is strongly associated with ATC. TR{beta} is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85. However, the role of TR{beta} in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TR{beta} indeed suppresses PI3K signaling in ATC through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TR{beta} in ATC enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TR{beta} but shed light into the implication of TR{beta} status and activation on inhibitor efficacy in ATC tumors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/379933v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@c1dc4aorg.highwire.dtl.DTLVardef@1659120org.highwire.dtl.DTLVardef@11ae63corg.highwire.dtl.DTLVardef@10196bd_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cancer biology↗

bioRxiv2019

Oncologic Therapy Shapes the Fitness Landscape of ClonalHematopoiesis

Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and gene-treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy-related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions.

genetics↗