ABSTRACT
ETV6::ABL1 is a rare fusion gene that found in MPN, ALL, and AML. It has a complex and diverse formation mechanism due to the reciprocal orientations of the ETV6 and ABL1 genes relative to the centromeres. NPM1 is frequently mutated in adult AML, often accompanied by FLT3-ITD, which suggests molecular synergisms in AML pathogenesis. Previous reports on ETV6::ABL1 mostly focus on FLT3-ITD. In this study, we present a case of AML with ETV6::ABL1, along with NPM1 and FLT3-ITD. The patient showed a rapid increase in primitive cells at the initial stage, along with the presence of immature granulocytes and erythrocytes. Through cytogenetic analysis, fluorescence in situ hybridization (FISH), and RNA-seq, we elucidated the mechanism behind the formation of the ETV6::ABL1 fusion gene. Despite conventional chemotherapy failure and rapid tumor proliferation, we attempted to add FLT3 inhibitor sorafenib to the treatment, along with chemotherapy bridging to haploidentical transplantation. After haplo-HSCT, a combination of sorafenib and dasatinib was administered as maintenance therapy. The patient achieved complete remission (CR) and maintained it for 11 months. The intricate genetic landscape observed in this case presents diagnostic dilemmas and therapeutic challenges, emphasizing the importance of a comprehensive understanding of its implications for disease classification, risk stratification, and treatment selection.
ABSTRACT
Auditory localization is a fundamental ability that allows to perceive the spatial location of a sound source in the environment. The present work aims to provide a comprehensive overview of the mechanisms and acoustic cues used by the human perceptual system to achieve such accurate auditory localization. Acoustic cues are derived from the physical properties of sound waves, and many factors allow and influence auditory localization abilities. This review presents the monaural and binaural perceptual mechanisms involved in auditory localization in the three dimensions. Besides the main mechanisms of Interaural Time Difference, Interaural Level Difference and Head Related Transfer Function, secondary important elements such as reverberation and motion, are also analyzed. For each mechanism, the perceptual limits of localization abilities are presented. A section is specifically devoted to reference systems in space, and to the pointing methods used in experimental research. Finally, some cases of misperception and auditory illusion are described. More than a simple description of the perceptual mechanisms underlying localization, this paper is intended to provide also practical information available for experiments and work in the auditory field.
ABSTRACT
BACKGROUND: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis. PROCEDURE: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML. RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells. CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
Subject(s)
Biomarkers, Tumor , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Child , Male , Female , Prognosis , Child, Preschool , Adolescent , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Infant , Survival Rate , Follow-Up Studies , East Asian People , rac GTP-Binding ProteinsABSTRACT
FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.
ABSTRACT
Hyperactive FMS-like receptor tyrosine kinase-3 mutants with internal tandem duplications (FLT3-ITD) are frequent driver mutations of aggressive acute myeloid leukemia (AML). Inhibitors of FLT3 produce promising results in rationally designed cotreatment schemes. Since FLT3-ITD modulates DNA replication and DNA repair, valid anti-leukemia strategies could rely on a combined inhibition of FLT3-ITD and regulators of cell cycle progression and DNA integrity. These include the WEE1 kinase which controls cell cycle progression, nucleotide synthesis, and DNA replication origin firing. We investigated how pharmacological inhibition of FLT3 and WEE1 affected the survival and genomic integrity of AML cell lines and primary AML cells. We reveal that promising clinical grade and preclinical inhibitors of FLT3 and WEE1 synergistically trigger apoptosis in leukemic cells that express FLT3-ITD. An accumulation of single and double strand DNA damage precedes this process. Mass spectrometry-based proteomic analyses show that FLT3-ITD and WEE1 sustain the expression of the ribonucleotide reductase subunit RRM2, which provides dNTPs for DNA replication. Unlike their strong pro-apoptotic effects on leukemia cells with FLT3-ITD, inhibitors of FLT3 and WEE1 do not damage healthy human blood cells and murine hematopoietic stem cells. Thus, pharmacological inhibition of FLT3-ITD and WEE1 might become an improved, rationally designed therapeutic option.
Subject(s)
Apoptosis , Cell Cycle Proteins , DNA Damage , Leukemia, Myeloid, Acute , Protein Kinase Inhibitors , Protein-Tyrosine Kinases , fms-Like Tyrosine Kinase 3 , Humans , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Apoptosis/drug effects , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Cell Line, Tumor , Drug Synergism , Animals , Pyrazoles , PyrimidinonesABSTRACT
Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3-ITD+ AML) still represents a challenge for modern hematology. Sorafenib is, to this date, the only inhibitor that demonstrated efficacy in improving both progression-free and overall survival as post-HCT maintenance therapy, even if its use in this setting has not been approved so far by regulatory agencies. The aim of our study was to evaluate the feasibility, safety, and efficacy of sorafenib maintenance in preventing early relapse in FLT3-ITD+ AML after HCT in a single-center experience. We analyzed 26 consecutive patients who received post-HCT 2-year maintenance with sorafenib at our center between 2017 and 2023. The median time from HCT to sorafenib start was 130 days, and the median dosage was 200 mg per day. Two (8%) and three (12%) patients discontinued maintenance due to toxicity and disease relapse, respectively. Eight (31%) patients terminated the 2-year maintenance and stopped sorafenib, while 13 patients are still under treatment. Overall, 21/26 patients (81%) are alive and in stable complete remission as outlined by a 2-year disease-free survival of 83.61%. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML.
ABSTRACT
Objective: This study aims to evaluate the safety and effectiveness of gilteritinib (Gilt) -based combination therapy bridging allo-HSCT for FLT3-ITD(+) R/R AML. Additionally, it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT. Methods: The clinical data of 26 patients with FLT3-ITD(+) R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed. The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS) time, disease-free survival (DFS) time, and adverse events experienced by all enrolled patients. Results: A total of 26 patients with FLT3-ITD(+) R/R AML were enrolled, including 14 men and 12 women with a median age of 38 (18-65) years. A total of 18 cases were refractory, and eight cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 26.9% (7/26), the CR with hematology incomplete recovery was 57.7% (15/26), and the partial response (PR) rate was 7.7% (2/26). The CRc was 84.6% (22/26), and the minimal residual disease (MRD) negativity rate was 65.4%. The 12 month cumulative OS rate for all patients was 79.0%, and the 24 month cumulative OS rate was 72.0%. The median OS time was not determined. The median follow-up time was 16.0 months. Among the patients who responded to treatment, the 12 month cumulative DFS rate was 78.0%, and the 24 month cumulative DFS rate was 71.0%. The median DFS time was not determined. Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT (3.3 months, 95%CI 2.2-4.3 months, P=0.005). The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined, but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment (P=0.019). The FLT3-ITD mutation clearance rate in this study was 38.5%, and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (15.0 months; P=0.018). The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia (76.9%), neutropenia (76.9%), febrile neutropenia (61.5%), thrombocytopenia (69.2%), and anemia (57.7%). One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment, but his condition improved after treatment. Conclusion: The Gilt-based combination therapy is highly effective in treating FLT3-ITD(+) R/R AML. It demonstrates a high CRc, MRD negativity rate, and rapid onset, leading to a significant improvement in patients' survival. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients' survival. Closely monitoring and managing any adverse event that may occur during treatment are crucial.
Subject(s)
Aniline Compounds , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Mutation , Pyrazines , fms-Like Tyrosine Kinase 3 , Humans , fms-Like Tyrosine Kinase 3/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Female , Adult , Hematopoietic Stem Cell Transplantation/methods , Middle Aged , Retrospective Studies , Pyrazines/administration & dosage , Adolescent , Aniline Compounds/therapeutic use , Aged , Young Adult , Transplantation, Homologous , Remission Induction , Disease-Free SurvivalABSTRACT
BACKGROUND: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro. METHODS: Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib. RESULTS: Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations. CONCLUSION: Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.
Subject(s)
Cell Proliferation , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute , Protein Kinase Inhibitors , fms-Like Tyrosine Kinase 3 , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Humans , Animals , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Cell Proliferation/drug effects , Mice , Xenograft Model Antitumor Assays , Apoptosis/drug effects , Mutation , Signal Transduction/drug effectsABSTRACT
Musicians perform better than non-musicians on a variety of non-musical sound-perception tasks. Whether that musicians' advantage extends to spatial hearing is a topic of increasing interest. Here we investigated one facet of that topic by assessing musicians' and non-musicians' sensitivity to the two primary cues to sound-source location on the horizontal plane: interaural-level-differences (ILDs) and interaural-time-differences (ITDs). Specifically, we measured discrimination thresholds for ILDs at 4 kHz (n =246) and ITDs at 0.5 kHz (n = 137) in participants whose musical-training histories covered a wide range of lengths, onsets, and offsets. For ILD discrimination, when only musical-training length was considered in the analysis, no musicians' advantage was apparent. However, when thresholds were compared between subgroups of non-musicians (<2 years of training) and extreme musicians (≥10 years of training, started ≤ age 7, still playing) a musicians' advantage emerged. Threshold comparisons between the extreme musicians and other subgroups of highly trained musicians (≥10 years of training) further indicated that the advantage required both starting young and continuing to play. In addition, the advantage was larger in males than in females, by some measures, and was not evident in an assessment of learning. For ITD discrimination, in contrast to ILD discrimination, parallel analyses revealed no apparent musicians' advantage. The results suggest that musicianship is associated with greater sensitivity to ILDs, a fundamental sound-localization cue, even though that sensitivity is not central to music, that this musicians' advantage arises, at least in part, from nurture, and that it is governed by a neural substrate where ILDs are processed separately from, and more malleably than, ITDs.
Subject(s)
Acoustic Stimulation , Auditory Threshold , Cues , Music , Sound Localization , Humans , Male , Female , Adult , Young Adult , Time Factors , Adolescent , Hearing , Age Factors , Middle Aged , Discrimination, PsychologicalABSTRACT
Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.
Subject(s)
Aniline Compounds , Cell Cycle Proteins , Drug Synergism , Leukemia, Myeloid, Acute , Metformin , Mutation , Polo-Like Kinase 1 , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins , Pyrazines , Signal Transduction , fms-Like Tyrosine Kinase 3 , Metformin/pharmacology , Metformin/therapeutic use , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Humans , Animals , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Signal Transduction/drug effects , Pyrazines/pharmacology , Pyrazines/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Mice , Mutation/genetics , Cell Line, Tumor , Thiophenes/pharmacology , Thiophenes/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , STAT5 Transcription Factor/metabolism , STAT5 Transcription Factor/genetics , Female , Xenograft Model Antitumor Assays , Male , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
During the treatment of 89 pediatric patients with Acute Myeloid Leukemia (AML) at the Hematology Department of Kunming Medical University's Children's Hospital from 2020 to 2023, three patients were identified to co-express the NUP98-NSD1, FLT3-ITD, and WT1 gene mutations. The bone marrow of these three patients was screened for high-risk genetic mutations using NGS and qPCR at the time of diagnosis. The treatment was administered following the China Children's Leukemia Group (CCLG)-AML-2019 protocol. All three patients exhibited a fusion of the NUP98 exon 12 with the NSD1 exon 6 and co-expressed the FLT3-ITD and WT1 mutations; two of the patients displayed normal karyotypes, while one presented chromosomal abnormalities. During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission. One patient underwent Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) and achieved complete molecular remission during a 12-month follow-up period. Regrettably, the other two patients, who did not receive transplantation, passed away. The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.
Subject(s)
Leukemia, Myeloid, Acute , Oncogene Proteins, Fusion , WT1 Proteins , fms-Like Tyrosine Kinase 3 , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , fms-Like Tyrosine Kinase 3/genetics , Male , Female , Child , Oncogene Proteins, Fusion/genetics , WT1 Proteins/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child, Preschool , Cytarabine/therapeutic use , Mutation , Nuclear Pore Complex Proteins/genetics , Hematopoietic Stem Cell Transplantation , Homoharringtonine/therapeutic use , InfantABSTRACT
BACKGROUND: FLT3 gene mutations are genetic abnormality that caused leukemogenesis. Furthermore, presence of FLT3 mutations is associated with poor prognosis in AML. This study aimed to identify FLT3 gene mutations so that it can be used as a genetic reference for the AML patients in Indonesian population. METHODS: This cross-sectional study recruited 63 AML de novo patients between August 2021 and July 2023 at Cipto Mangukusumo General Hospital and Dharmais Cancer Hospital. We collected peripheral blood from the patients for DNA isolation. FLT3 gene mutation was detected using PCR method, then followed by the Sanger sequencing. Novel mutation in exon-14 continued to in silico study using SWISS MODEL server for modelling protein and PyMOL2 software for visualizing the protein model. RESULTS: Frequency FLT3-ITD mutation was 22% and 6 (10%) patients had a novel mutation on juxtamembrane domain. The number of FLT3-ITD insertions was 24 bp to 111 bp, with a median of 72 bp. Novel mutation indicated a change in the protein sequence at amino acid number 572 from Tyrosine to Valine and formed a stop codon (UGA) at amino acid position ins572G573. In-silico study from novel mutation showed the receptor FLT3 protein was a loss of most of the juxtamembrane domain and the entire kinase domain. CONCLUSION: A novel FLT3 gene mutation was found in this study in the juxtamembrane domain. Based on the sequencing analysis and in silico studies, this mutation is likely to affect the activity of the FLT3 receptor. Therefore, further studies on this novel mutation are needed.
Subject(s)
Leukemia, Myeloid, Acute , Mutation , fms-Like Tyrosine Kinase 3 , Humans , fms-Like Tyrosine Kinase 3/genetics , Leukemia, Myeloid, Acute/genetics , Male , Female , Mutation/genetics , Middle Aged , Adult , Cross-Sectional Studies , Aged , Indonesia , Protein Domains/genetics , Young Adult , Exons/genetics , AdolescentABSTRACT
FLT3-ITD is a type of poor prognostic factors in acute myeloid leukemia (AML) disease. Gilteritinib, the second-generation FLT3 tyrosine kinase inhibitor, improved the overall survival of patients with relapsed/refractory FLT3-mutated AML in the ADMIRAL phase III trial. However, few data are available on the efficacy and safety of gilteritinib-based therapy for FLT3-mutated AML with central nervous system (CNS) involvement. We performed gilteritinib to treat a patient with CNS relapsed AML after allogeneic hematopoietic stem cell transplantation. The positive antileukemic effect of gilteritinib may bring new hope for the treatment of FLT3-mutated AML with CNS relapse.
ABSTRACT
Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAFV600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.
Subject(s)
Erdheim-Chester Disease , Leukemia, Myeloid, Acute , Mutation , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , fms-Like Tyrosine Kinase 3 , Humans , Erdheim-Chester Disease/genetics , Erdheim-Chester Disease/complications , Erdheim-Chester Disease/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/diagnosis , fms-Like Tyrosine Kinase 3/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Male , Clonal Evolution/genetics , Female , Proto-Oncogene Proteins B-raf/genetics , Middle AgedABSTRACT
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like tyrosine kinase 3 ligand gene (FLT3-ITD) represents an important factor in the prognosis of AML. The objective of this study was to determine for the first time the prevalence of FLT3-ITD mutation in west Algerian AML patients. A total of 160 AML patients were genotyped for FLT3-ITD mutation by using polymerase chain reaction. FLT3-ITD mutation was detected in 13% of patients. Mutation rates show no significant difference in the distribution of sex and age. A positive association was found between this mutation and a higher leukocyte and blast cells counts. We also found that the M3 and M5 subtype were the commonest in the FLT3 mutated group. This preliminary study provides first-time prevalence estimates for FLT3-ITD mutation in acute myeloid leukemia patients from the West region of Algeria.
ABSTRACT
Sarcomas characterized by BCOR gene alterations, are a distinct clinico-pathological group of high-grade tumors, that represent 5% of small round cell tumors without EWSR or FUS fusion. Diverse genetic alterations characterize this group, including BCOR-CCNB3 gene fusion being the most common alteration and less frequently internal tandem duplications (ITDs). We present a compelling case of a 3-year-old girl diagnosed with a high-grade nasoethmoidal sarcoma exhibiting BCOR-ITD. The diagnostic process illustrates the histological and immunophenotypic spectrum, requiring an extensive immunohistochemical panel and diverse molecular tests for accurate classification. Additionally, this case highlights the challenges in detecting BCOR-ITDs using different NGS panels, advocating for alternative molecular approaches. Our patient after 10 months since diagnosis is alive with progressive disease. This emphasizes the urgency for ongoing research to refine diagnostic methods and develop effective therapeutic strategies for these rare and aggressive tumors.
ABSTRACT
The central nervous system tumor with BCL-6 interacting corepressor internal tandem duplication (BCOR-ITD) is a molecularly defined entity with an internal tandem duplication in exon 15 of the BCOR gene. It is histologically characterized by a solid pattern with spindle-shaped cells and a dense capillary network. Very few cases of this rare entity have been reported till date. We present a case of BCOR-positive CNS tumor in a 3-year-old child who presented with scalp swelling. A differential diagnosis of CNS tumor with BCOR expression should be considered whenever high-grade tumors with histopathological features of glial or ependymal tumors do not express the classical glial markers.
ABSTRACT
Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Mutation , Sulfonamides , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3 , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/metabolism , Humans , Animals , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Sulfonamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Mice , Cell Line, Tumor , Pyrazines/pharmacology , Drug Synergism , Aniline Compounds/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Proteolysis/drug effects , Female , Protein Kinase Inhibitors/pharmacologyABSTRACT
Combining cochlear implants with binaural acoustic hearing via preserved hearing in the implanted ear(s) is commonly referred to as combined electric and acoustic stimulation (EAS). EAS fittings can provide patients with significant benefit for speech recognition in complex noise, perceived listening difficulty, and horizontal-plane localization as compared to traditional bimodal hearing conditions with contralateral and monaural acoustic hearing. However, EAS benefit varies across patients and the degree of benefit is not reliably related to the underlying audiogram. Previous research has indicated that EAS benefit for speech recognition in complex listening scenarios and localization is significantly correlated with the patients' binaural cue sensitivity, namely interaural time differences (ITD). In the context of pure tones, interaural phase differences (IPD) and ITD can be understood as two perspectives on the same phenomenon. Through simple mathematical conversion, one can be transformed into the other, illustrating their inherent interrelation for spatial hearing abilities. However, assessing binaural cue sensitivity is not part of a clinical assessment battery as psychophysical tasks are time consuming, require training to achieve performance asymptote, and specialized programming and software all of which render this clinically unfeasible. In this study, we investigated the possibility of using an objective measure of binaural cue sensitivity by the acoustic change complex (ACC) via imposition of an IPD of varying degrees at stimulus midpoint. Ten adult listeners with normal hearing were assessed on tasks of behavioral and objective binaural cue sensitivity for carrier frequencies of 250 and 1000 Hz. Results suggest that 1) ACC amplitude increases with IPD; 2) ACC-based IPD sensitivity for 250 Hz is significantly correlated with behavioral ITD sensitivity; 3) Participants were more sensitive to IPDs at 250 Hz as compared to 1000 Hz. Thus, this objective measure of IPD sensitivity may hold clinical application for pre- and post-operative assessment for individuals meeting candidacy indications for cochlear implantation with low-frequency acoustic hearing preservation as this relatively quick and objective measure may provide clinicians with information identifying patients most likely to derive benefit from EAS technology.
Subject(s)
Acoustic Stimulation , Auditory Threshold , Cochlear Implantation , Cochlear Implants , Cues , Sound Localization , Speech Perception , Humans , Female , Male , Cochlear Implantation/instrumentation , Adult , Middle Aged , Electric Stimulation , Audiometry, Pure-Tone , Persons With Hearing Impairments/psychology , Persons With Hearing Impairments/rehabilitation , Time Factors , Aged , Noise/adverse effects , Perceptual Masking , Young Adult , Hearing , PsychoacousticsABSTRACT
Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3â¯bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.