Biology subjects

Celik, H.

Publications and source records attributed to Celik, H..

5 recordsLinked to original sources

bioRxiv2025

Bronsted-basic small molecules activate GTP hydrolysis in Ras Q61 mutants

The RAS oncogenes (KRAS, HRAS, NRAS) are among the most frequently mutated genes in human cancer, affecting over three million patients annually. Therapeutic development has largely focused on inhibitors for KRAS codon 12 mutations (G12C/D/V/S/R) which are key drivers in lung, colorectal, and pancreatic cancers. In contrast, mutant-selective inhibitors for Q61 variants remain elusive. A common mechanistic feature of G12 and Q61 mutants is the impaired hydrolysis of GTP, which traps Ras in its active, signaling-competent state. We envisioned that an alternative therapeutic strategy - reactivation of GTP hydrolysis - could address this shared oncogenic mechanism. Here we report small molecules that accelerate GTP hydrolysis in K-Ras Q61 mutants. These compounds compensate for the loss of the catalytic residue Gln61 by introducing a general base into the active site, selectively enhancing hydrolysis of K-Ras Q61X (X = H, L, K, R) mutants by up to 20-fold while sparing the wild-type protein. In mutant cancer cell lines, these compounds reduce GTP-bound Ras levels and suppress downstream signaling. We show that the chemical design principles are generalizable to other Ras isoforms. This work establishes a mechanistic foundation for small-molecule "GTPase activators" and offers a new paradigm for targeting Ras-driven cancers.

cancer biology↗

bioRxiv2025

JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation

Hematopoietic stem cell transplantation is a common treatment for many blood disorders and can be a life-saving therapy for patients with leukemias, lymphomas and multiple myeloma. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that genetic deletion of the polycomb repressive complex 2 (PRC2) co-factor Jarid2 in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through JARID2 inhibition. In this study, we demonstrate that both constitutive and transient knockdown of JARID2 increases the number and enhances the functionality of human HSPCs both in vitro and in vivo. This phenotype was distinct from inhibition of EZH2 in UCB cells, suggesting the mechanism was independent of PRC2 co-factor activity of JARID2. Mechanistically, JARID2 knockdown promotes a quiescent, long-term self-renewal gene expression program governed by upregulating STAT1 and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs in vivo. Taken together, these findings highlight JARID2 inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population. One Sentence SummaryGenetic inhibition of JARID2 enhances repopulating activity of human hematopoietic stem and progenitor cells in vivo via STAT1 upregulation.

developmental biology↗

bioRxiv2022

Reliability metrics of outcome measures during the single and double leg drop jump tests

Although a number of previous studies have studied reliability metrics of outcome measures during single and double leg drop jump tests, none of them presented detailed reliability information for both tests with a group of collegiate athletes of both genders. The aim of this study was therefore to assess the reliability of outcome measures during the single and double leg drop jump tests with proper reliability metrics. Seventeen handball players (11 male and 6 female) participated in the experiments. Each player performed three double leg and three single drop jumps from a 30 cm height box onto a portable force plate in two sessions a week apart. Sixteen outcome measures, including jump height (JH), ground contact time (GCT), reactive strength index (RSI), were calculated. Four groups of reliability metrics like absolute agreement and consistency intraclass correlation coefficients (inter-day and intra-day), standard error of measurement, coefficient of variation, and minimal metrically detectable change were estimated for reliability assessment. The outcome measures as RSI and its individual components JH and GCT together with normalized vertical stiffness (Kvert) yielded high inter-day and intra-day intraclass correlation coefficients and low standard error of measurement and coefficient of variation levels for the double leg drop jump test. The more challenging single leg drop jump test could also be considered reproducible with some other highly reliable outcome measure set by keeping JH, GCT, and normalized Kvert and replacing vertical jump impulse with RSI. The results of the current study therefore suggested the drop jump tests could be deemed reliable to be used for short-term and long-term monitoring needs for a group of collegiate athletes of both genders.

physiology↗

bioRxiv2021

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.

cancer biology↗

bioRxiv2020

A Humanized Animal Model Predicts Clonal Evolution and Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are chronic blood diseases with significant morbidity and mortality. While sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically-engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDXs). These PDXs robustly engrafted patient cells which recapitulated the patients genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify MF patients at-risk for sAML transformation, and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology. STATEMENT OF SIGNIFICANCEAlthough the genetic events driving myeloproliferative neoplasms (MPNs) are well-defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a patient-derived xenograft (PDX) system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacological manipulation.

cancer biology↗