Inactivation of oncogenic BCR::ABL1 by imatinib in the early chronic phase (CP) of chronic myeloid leukemia (CML) has achieved unprecedented clinical success, which eludes the majority of terminal blast crisis (BC) patients, predominantly due to the scantily understood BCR::ABL1-independent mechanism/s of resistance. Our earlier proteomic studies on K562 and KU812 cell lines, which mimicked the BCR::ABL1-independent resistance to imatinib reported in CML patients, demonstrated that atypical activation of signalling downstream of imatinib-inactivated BCR::ABL1, mediated by reduced levels of cell adhesion receptor - integrin ITGB1, caused resistance. In the present study, events upstream of ITGB1 were derived from the transcriptome, methylome, and miRNA profiles of imatinib-resistant cell lines. The analyses identified major alterations in cell adhesion pathway molecules in resistant cells. Significant among them were gene hypomethylation, upregulation of the transcript and protein of ITGB3, known to influence the protein level of ITGB1, which was reduced despite unaltered gene methylation and transcription. Indeed, knockdown (KD) of ITGB3 caused augmentation of ITGB1 protein level. Further, the mediator of ITGB3 overexpression was detected in genomic analysis. A recurrent gain at chromosomal region 8q11.21-12.1 and amplification of the transcription factor PLAG1 residing therein were observed in resistant K562 cells and CD34 + cells from resistant BC patients. KD of PLAG1 not only reversed gene hypomethylation, upregulation of transcript and protein of ITGB3 but also restored ITGB1 level and sensitized resistant cells to imatinib. The study has identified events upstream of ITGB1, thereby advancing the understanding of BCR::ABL1-independent imatinib resistance and has provided explorable therapeutic avenues for imatinib-resistant blast phase CML.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive soft tissue tumor, and its occurrence in the vulva is exceptionally rare. We describe the case of a 35-year-old woman who presented with a recurrent vulvar mass one year after excision of a lesion previously diagnosed as aggressive angiomyxoma. Histopathological examination of the recurrent lesion demonstrated spindle cell proliferation within a myxoid stroma, focal storiform architecture, and honeycomb infiltration of the subcutaneous adipose tissue, findings that were morphologically consistent with myxoid dermatofibrosarcoma protuberans. Because immunohistochemical and molecular testing were unavailable, definitive pathological confirmation could not be established. The patient underwent wide local excision followed by reconstruction with a split-thickness skin graft. Histopathological examination demonstrated involvement of the deep surgical margin. After multidisciplinary discussion, adjuvant imatinib (400 mg once daily) was initiated for 12 months because additional surgery was considered likely to result in significant anatomical and functional morbidity. No evidence of local recurrence was observed during 12 months of follow-up. This case highlights the diagnostic uncertainty and treatment challenges associated with rare vulvar mesenchymal tumors in resource-limited settings and underscores the importance of clinicopathologic correlation, individualized multidisciplinary management, and long-term clinical follow-up.

The molecular interpretation of eosinophilic neoplasms harboring t(5;12) may be challenging because cytogenetic breakpoint assignments can suggest a PDGFRB rearrangement without identifying the underlying fusion. We retrospectively investigated a woman with a chronic eosinophilic myeloid neoplasm initially investigated in 2002, in whom a subsequent t(5;12)(q31 ~ q33;p13) raised suspicion of PDGFRB involvement. Contemporary molecular investigations failed to identify the rearrangement, and an empiric trial of imatinib produced no meaningful hematologic response. Seventeen years later, blast transformation was accompanied by persistence of t(5;12) and acquisition of del(9)(q22). Fluorescence in situ hybridization demonstrated ETV6 rearrangement but no PDGFRB break-apart pattern, indicating en bloc translocation of the PDGFRB locus. Targeted RNA sequencing of archived RNA extracted from cryopreserved peripheral blood cells collected in 2004 subsequently identified a strong-evidence ETV6::ACSL6 fusion joining exon 2 of ETV6 to exon 2 of ACSL6, supported by 1847 reads and 218 unique start sites. Targeted myeloid DNA sequencing detected no mutation within the regions analyzed. Identification of ETV6::ACSL6 shifted the biological interpretation away from presumed constitutive tyrosine kinase activation toward a proposed cytokine regulatory rewiring involving the 5q31 cytokine locus, consistent with published experimental evidence and the absence of response to imatinib. This case illustrates how contemporary RNA-based fusion detection can resolve a historically uncharacterized structural rearrangement and refine biological interpretation and therapeutic expectations, while documenting an unusually prolonged natural history of an ETV6::ACSL6-associated eosinophilic myeloid neoplasm.

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 cm[2]) 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.