The BCR-ABL fusion protein with dysregulated tyrosine kinase activity is the cause of chronic myelogenous leukemia (CML). Mutations in the P-loop, gatekeeper, catalytic and activation loop, within its kinase domain leads to drug resistance while treating CML. The mutation driven drug resistance mechanisms at the atomic level in BCR-ABL needs to be unravelled. This work aims to study the structural, dynamical, and functional effects of the P-loop point mutations on BCR-ABL kinase. In this work, the five main FDA approved drugs Imatinib, Dasatinib, Nilotinib, Ponatinib, Bosutinib and one investigational drug Rebastinib were analysed using molecular dynamics (MD), post-MD analyses and quantum chemical (QM) approaches. The P-loop residue L248 and its point mutations (L248R/V) forming direct interactions with the drug were validated. The root-mean-square deviation analysis suggests that Imatinib, Dasatinib and Nilotinib are promising drugs for L248 and L248R/V point mutations, followed by Rebastinib, Ponatinib, and Bosutinib, despite minor variations. The R and C-spines of the wild and mutant systems differ significantly, indicating that the protein backbone is directly affected by mutation. For all the considered wild and mutated amino acid-drug complexes, the interaction energy for L248R complexes is high compared to L248 and L248V complexes. The frontier molecular orbitals, HOMO-LUMO gap, and electrostatic potential maps were analysed. The MD simulations and QM studies suggest that L248 residue and its point mutations (L248R/V) are responsible for high affinity binding of BCR-ABL kinase with the drugs considered for the study.

Therapeutic drug monitoring (TDM) of imatinib (IMB), a first-line tyrosine kinase inhibitor, is clinically essential due to its narrow therapeutic window and significant inter-individual pharmacokinetic variability. Existing analytical methods for IMB quantification suffer from limitations including high operational costs, complex sample preparation, toxicity concerns (mercury-based electrodes), and time-consuming procedures. This study describes the first-ever fabrication and application of a novel electrochemical sensor based on a terbium-modified polymerized diphenylamine orange composite on a pencil graphite electrode (Tb@poly-DPO/PGE) for sensitive, selective, and sustainable determination of IMB. The Tb@poly-DPO/PGE sensor was fabricated via sequential electropolymerization of DPO onto PGE followed by electrodeposition of Tb ions. The sensor was characterized using scanning electron microscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. The Tb@poly-DPO/PGE sensor exhibited superior electrochemical performance with significantly enhanced electroactive surface area (0.175 cm2) and reduced charge-transfer resistance (112.0 Ω). Density functional theory (DFT) calculations were employed to investigate molecular-level interactions. A square-wave voltammetric (SWV) method was developed and validated according to ICH and EMA guidelines for IMB quantification in bulk solutions and spiked human plasma samples. The SWV method demonstrated linear response in two concentration ranges (0.025-0.5 μM and 1.0-4.5 μM) with a detection limit of 5.46 nM. The method showed acceptable trueness (recovery: 99.91-100.46%), precision (RSD ≤ 1.14%), selectivity, and stability over 20 days. Successful application to spiked human plasma samples demonstrated minimal matrix effects. The proposed method demonstrated superior analytical throughput (15 samples/hour in batch mode) and sustainability, achieving an Environmental, Performance, and Practicality Index score of 78.2. The fabricated sensor provides a robust, environmentally sustainable, and practically feasible platform for routine TDM of IMB, offering a promising alternative to existing analytical methodologies pending further validation on authentic patient samples.

Idiopathic pulmonary fibrosis is a chronic, progressive fibrosing interstitial lung disease with a poor prognosis, carrying a median survival of two to three years without antifibrotic therapy. Nintedanib, an oral intracellular tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFRs 1-3), platelet-derived growth factor receptor (PDGFR)-α/β, and fibroblast growth factor receptors (FGFRs) 1-3, has emerged as a cornerstone of therapy, reducing the rate of forced vital capacity (FVC) decline by approximately 50% in the INPULSIS trials. While diarrhea is the most common adverse event, generalized body swelling has not been previously described with nintedanib, although it is a well-recognized class effect of several oncologic TKIs, including imatinib and mesenchymal-epithelial transition factor (MET) inhibitors. We report a 66-year-old male ex-smoker with a 45-pack-year smoking history and comorbidities including ischemic heart disease, bronchial asthma, and gastroesophageal reflux disease who presented with five months of progressive dyspnea, classified as modified Medical Research Council grade III. High-resolution computed tomography revealed bilateral peripheral reticulation with mild honeycombing, traction bronchiectasis, and basal predominance without ground-glass opacities, fulfilling the criteria for a definite usual interstitial pneumonia pattern. Spirometry demonstrated a moderate restrictive pattern (FVC, 65%), and autoimmune screening was comprehensively negative. Following multidisciplinary review, nintedanib was initiated at 100 mg twice daily and subsequently escalated to the standard 150 mg twice-daily dose. The patient developed mild generalized body swelling at initiation, which worsened markedly after dose escalation. Extensive cardiology, nephrology, endocrine, hepatic, and metabolic evaluations identified no alternative cause. Discontinuation of nintedanib resulted in near-complete resolution of swelling within two months. Rechallenge at a tertiary interstitial lung disease center precipitated recurrence of identical generalized swelling within one month, necessitating a second discontinuation. The temporal relationship, dose dependence, and reproducible recurrence on rechallenge strongly suggest a causal association between nintedanib and generalized body swelling in this patient. This previously unreported adverse event warrants clinician vigilance and formal pharmacovigilance reporting.

Tyrosine kinase inhibitors (TKI) have transformed chronic myeloid leukemia (CML) from a life-threatening disease into a manageable chronic condition. However, 30-50% of patients require TKI switching due to resistance or intolerance, and BCR::ABL1-independent resistance mechanisms remain the most frequent and least understood cause. Non-coding RNAs (ncRNAs) - including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - have emerged as regulators of TKI resistance. This scoping review aimed to characterize the role of ncRNAs in TKI resistance, and to evaluate their potential as biomarkers and therapeutic targets. A systematic literature search was performed in PubMed/MEDLINE in April 2026, supplemented by manual reference searching. Of 374 identified records, 25 studies published between 2021 and 2025, plus one 2020 study identified through manual searching were included. miRNAs were the most frequently evaluated (64%), followed by lncRNAs (16%) and circRNAs (12%), with imatinib as the predominant TKI studied. Four axes were identified for miRNAs: downstream BCR::ABL1 signaling regulation, the miR-185/PAK6 axis, apoptosis and protective autophagy modulation, and drug efflux mechanisms. circRNAs and lncRNAs were found to act as competing endogenous RNAs regulating resistance via PI3K/AKT/mTOR, RAS/MAPK, and autophagy pathways. Prospective multicenter validation, particularly in countries with limited access to second- and third-generation TKIs, is a priority for future research.

Primary familial gastrointestinal stromal tumors (GIST) are characterized by the presence of typically multifocal GIST that most often involve the stomach. Additional gastrointestinal (GI) manifestations can include inflammatory fibroid polyps most often in the stomach or small bowel and interstitial cell of Cajal hyperplasia occurring throughout the GI tract. Skin hyperpigmentation typically involving the neck, face, axillae, groin, and perineum that appears in childhood or adolescence is common. Additional integument findings can include increased nevi, lentigines, and multiple café au lait macules. Less common features include urticaria pigmentosa, cutaneous mastocytosis, and systemic mastocytosis.

The stem cell factor (SCF)/KIT signaling axis regulates the survival, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, mast cells, interstitial cells of Cajal, germ cells, and melanocytes through multiple downstream pathways, including PI3K/AKT and RAS/MAPK. Its biological and pathological effects are determined by cell lineage, ligand presentation, and mutational context. At the pathway level, SCF expression and processing, KIT abundance, and activating mutations determine signal initiation and intensity, whereas CBL-mediated receptor degradation and SHP-1-mediated dephosphorylation limit signal duration. This narrative review critically examines representative multisystem diseases for which SCF/KIT involvement is supported by genetic, functional, or therapeutic evidence and distinguishes established treatments from investigational approaches. Activating KIT mutations drive gastrointestinal stromal tumors (GISTs) and systemic mastocytosis. Clinically established KIT-directed tyrosine kinase inhibitors, including imatinib for mutation-sensitive GIST and midostaurin or avapritinib for advanced systemic mastocytosis, have transformed disease management. By contrast, increased local SCF availability and KIT-dependent mast cell persistence may amplify inflammatory diseases, whereas impaired signaling is associated with gastrointestinal dysmotility, reproductive dysfunction, and pigmentary abnormalities. Emerging anti-KIT antibodies are being investigated as a strategy to deplete mast cells in chronic urticaria, whereas recombinant SCF-based mobilization has largely historical clinical relevance and regenerative applications remain experimental. Mutation-dependent drug sensitivity, polyclonal secondary resistance, multikinase-related toxicity, and on-target effects in normal KIT-dependent tissues remain major challenges. A disease-, genotype-, and cell-specific framework is therefore essential for translating SCF/KIT biology into safe and effective precision therapies.

Periorbital hyperpigmentation (POH) as the sole initial manifestation remains undescribed in patients with smoldering multiple myeloma (SMM) without amyloid deposition, and the coexistence of SMM with gastrointestinal stromal tumor (GIST) is exceptionally rare. We describe a 56-year-old male who was treated with imatinib for eight months after resection of a low-risk gastric GIST and developed bilateral symmetric POH. Workup revealed IgA κ-type monoclonal gammopathy and 3% abnormal plasma cells on bone marrow aspiration. Further biopsies of bone marrow and abdominal wall fat excluded amyloid deposition. Therefore, a diagnosis of SMM (IgA κ-type) was made. To the best of our knowledge, this is the first reported case of SMM presenting with isolated POH in the absence of light-chain (AL) amyloidosis and coexisting with a GIST. This case suggests that POH may represent a rare early cutaneous manifestation of SMM and may further broaden the recognized clinical spectrum of SMM.

Duffy-null-associated neutrophil count (DANC) refers to a below-normal absolute neutrophil count (ANC < 1.5 × 10[3]/L), present most commonly in African American individuals. Neutropenia is a result of a lack of Fya and Fyb antigens on red blood cells. These patients do not have an increased risk of infection and may have an ANC < 1.5 × 10[3]/L at baseline. This unique case presents Duffy-null-associated neutropenia in the setting of chronic myeloid leukemia (CML). A 64-year-old African American female presented to the emergency department on May 17, 2021, for fatigue and was found to have a white blood cell (WBC) count of 65.3 × 10[9]/L. Hematology and oncology referral led to a diagnosis of CML. Subsequently, she began treatment with imatinib (Gleevec) 400 mg daily. One month into treatment, she was neutropenic, with an ANC of 0.6 × 10[3]/L. For the next several years, this patient repeatedly had treatment holds and dose reductions in response to recurrent neutropenia. When BCR-ABL1 transcript level continued to increase, indicating poor treatment response, she was referred to Medical University of South Carolina (MUSC). After several treatment changes due to adverse effects, she began treatment with asciminib 80 mg daily. BCR-ABL1 transcript level with asciminib was consistently below 0.1%, indicating successful treatment response. Despite this milestone, she continued to have episodes of neutropenia, prompting a check for Duffy antigen presence. Testing confirmed the lack of Fya and Fyb antigens, indicating Duffy-null status. This case demonstrates the importance of identifying Duffy-null individuals. Despite achieving major molecular response, the patient had persistent neutropenia, leading to the investigation of Duffy-null status. It is hypothesized that underlying Duffy-null status may have caused neutropenia, rather than an adverse reaction to treatment. Early detection of Duffy-null status can prevent dose reductions in therapy and delayed remission. Particularly with African American patients, a better framework for addressing Duffy-null neutropenia may benefit long-term outcomes in the setting of cancer therapy.