[Primary cardiac synovial sarcoma: a clinicopathological analysis of five cases].

Objective: To assess the clinicopathological features, immunophenotype, molecular characteristics and differential diagnosis of primary cardiac synovial sarcoma (PCSS). Methods: Five cases of PCSS were collected at Guangdong Provincial People's Hospital from 2008 to 2023, and their clinicopathological features were summarized. Immunohistochemical staining, fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) were performed, and relevant literatures were reviewed. Results: The cases were found in four males and one female, ranging in ages from 16 to 51 years (median 30 years). Two cases were located in the pericardium, two in the right ventricle, and one in the left ventricle. Follow-up data were available in four cases. All the four patients died of disease at 3, 7, 13 and 26 months, respectively, after diagnosis. The tumor maximum diameter ranged from 6.0 to 14.0 cm in (mean 10.0 cm). Microscopically, three cases were monophasic and two cases were biphasic. Immunohistochemically, all cases were immunoreactive for EMA, vimentin, bcl-2 and CD56. The tumor cells were variably positive for pan-cytokeratin, SS18-SSX, SOX2, TLE1, CD99, synaptophysin, calretinin and calponin. FISH showed the presence of SS18 rearrangement in all the cases. NGS detected SS18-SSX gene fusion in three cases (SS18-SSX1 in one and SS18-SSX2 in two). Conclusions: PCSS is an exceedingly rare neoplasm, and should be distinguished from other various malignant epithelial and mesenchymal tumors. The clinical history, histopathological and immunohistochemical features, and molecular findings are all essential to the definitive diagnosis of PCSS.

[Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion]. / Pervichnaya legochnaya miksoidnaya sarkoma so sliyaniem genov EWSR1-CREB1.

Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion is an extremely rare tumor. Its clinical manifestation is unspecific and only molecular genetic method can proof this diagnosis. This paper describes an unusual clinical presentation of primary pulmonary myxoid sarcoma in a 68-year-old patient with involvement of both lungs.

[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

An unusual case of primary splenic soft part alveolar sarcoma: case report and review of the literature with emphasis on the spectrum of TFE3-associated neoplasms.

BACKGROUND: Alveolar soft part sarcoma is a rare tumour of soft tissues, mostly localized in muscles or deep soft tissues of the extremities. In rare occasions, this tumour develops in deep tissues of the abdomen or pelvis. CASE PRESENTATION: In this case report, we described the case of a 46 year old man who developed a primary splenic alveolar soft part sarcoma. The tumour displayed typical morphological alveolar aspect, as well as immunohistochemical profile notably TFE3 nuclear staining. Detection of ASPSCR1 Exon 7::TFE3 Exon 6 fusion transcript in molecular biology and TFE3 rearrangement in FISH confirmed the diagnosis. CONCLUSION: We described the first case of primary splenic alveolar soft part sarcoma, which questions once again the cell of origin of this rare tumour.

Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population.

OBJECTIVE: To ascertain the frequency of the MLL::AF9 gene rearrangement and its association with survival in Pakistani patients suffering from acute myeloid leukaemia (AML). STUDY DESIGN: Analytical study. Place and Duration of the Study: Department of Haematology, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan, from 2015 to 2020. METHODOLOGY: Patients without a history of past AML chemotherapy, aged from 10 to 75 years, were included. Individuals with metastatic cancer, chronic myeloid leukaemia, or other haematological conditions were excluded. Identifying the MLL::AF9 gene involved RNA extraction, cDNA synthesis, and Real-time PCR amplification. The Chi-square test was used to examine the relationship between survival and the MLL::AF9 mutation. A Welch two-sample t-test was used to evaluate survival days depending on the MLL::AF9 gene rearrangement, while ANOVA was used to analyse survival days across various death statuses. RESULTS: The mean age of 130 patients was 36.65 ± 13.01 years, with 64.62% being males. The most common leukaemia type was AML-M2 (n = 32, 24.62%). During the study follow-up, 22.31% were still alive, 40.77% died, and the status of 36.92% were unknown. MLL::AF9 gene rearrangement was present in 11.54%. The group with MLL::AF9 gene rearrangement had significantly longer mean 'survival days' (1,542.33 ± 926.07) compared to the group without the gene rearrangement (206.42 ± 359.57, p <0.001). CONCLUSION: MLL-AF9 mutation was present in 11.54%. Age and MLL::AF9 gene rearrangement were significant predictors of survival in leukaemia patients. KEY WORDS: Acute myeloid leukaemia, MLL::AF9, Gene rearrangement, Survival.

Abdominopelvic desmoplastic small round cell tumor with metastasis: A case report and literature review.

RATIONALE: Desmoplastic small round cell tumor (DSRCT) is a rare and rapidly metastasizing soft tissue sarcoma, distinguished by its unique cell morphology and pleomorphic differentiation. PATIENT CONCERNS: This report describes the case of an 18-year-old male diagnosed with abdominopelvic DSRCT exhibiting metastases to the peritoneum, liver, pleura, bone, and muscle. The patient primarily presented with symptoms of incomplete intestinal obstruction and an abdominal mass. DIAGNOSES: Colonoscopy revealed lumen stenosis caused by external compression mass. Contrast-enhanced computed tomography and 18F-fluorodeoxyglucose positron emission tomography/computed tomography revealed multiple lesions in the abdominopelvic cavity. A needle biopsy of an abdominal wall lesion established it as a malignant tumor, origin unknown. Immunohistochemical staining post-surgery showed positive results for Cytokeratin (CK), CK7, Desmin, Vimentin, Caudal type homeobox 2 (CDX2), and Ki-67. Fluorescence in situ hybridization analysis revealed an Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1 (EWSR1) rearrangement, and next-generation sequencing identified an EWSR1-Wilms tumor protein 1 (WT1) gene fusion. INTERVENTIONS: The patient underwent laparoscopic exploratory surgery, which encompassed biopsy, ascites drainage, adhesion lysis, reinforcement of weakened sections of the small intestinal walls, and repositioning of twisted intestines. Postoperatively, the treatment protocol included fasting, rehydration, gastrointestinal decompression, and parenteral nutrition. However, the patient did not received chemotherapy. OUTCOMES: The patient declined further treatment and deceased in early November. LESSONS: This case highlights the nonspecific nature of DSRCT symptoms. In clinical practice, it is crucial to meticulously evaluate unexplained intestinal obstruction in young patients, considering DSRCT as a differential diagnosis to avoid delays in diagnosis.

Primary NTRK -rearranged Spindle Cell Neoplasm of the Gastrointestinal Tract: A Clinicopathological and Molecular Analysis of 8 Cases.

NTRK-rearranged spindle cell neoplasm occurs predominantly in the superficial or deep soft tissues of extremities or trunk. Occurrence in the visceral organs is extremely rare. Herein, we describe 8 cases of NTRK-rearranged spindle cell neoplasm that arose primarily in the gastrointestinal tract. Patients included 5 males and 3 females with age at presentation ranging from 6 to 63 years (median: 29.5 years). Tumors occurred in the colon (n=3), small intestine (n=2), rectum (n=2), and stomach (n=1). Tumor size ranged from 3.5 to 9 cm (median: 5 cm). Morphologically, 4 tumors were low-grade, composed of haphazard or intertwining fascicles of spindle cells, with prominent interstitial collagen fibers and ring-like perivascular hyalinization being present in 2 tumors. The other 4 tumors were histologically high-grade sarcomas, consisting of sweeping fascicles of atypical spindle cells showing increased cellularity and brisk mitotic activity. Immunohistochemically, 6/6 cases (100%) showed diffuse and strong cytoplasmic staining of pan-TRK. Variable expression of TrkA, CD34, and S100 was noted in 5/5 (100%), 5/8 (62.5%), and 4/7 (57.1%) cases, respectively. Fluorescence in situ hybridization analysis showed NTRK1 rearrangement (n=7) and NTRK2 rearrangement (n=1). In cases with available materials, RNA sequencing identified LMNA::NTRK1 (n=3), TPM3::NTRK1 (n=2), and STRN::NTRK2 (n=1) fusions. At follow-up (range: 4 to 30 months; median: 12.5 months), 6 of 7 patients who underwent surgery had no evidence of disease at last follow-up. One patient was succumbed to the disease at 12 months despite adjunctive treatment with TRK inhibitor larotrectinib after surgery. One patient was treated with larotrectinib alone. He showed significant response at 7 months after treatment. NTRK-rearranged spindle cell neoplasm represents an exceptionally rare entity in the gastrointestinal tract. The presence of interstitial collagen fibers and ring-like perivascular hyalinization and co-expression of CD34 and S100 are diagnostic clues to low-grade neoplasms. However, high-grade sarcomas pose a considerable diagnostic challenge to pathologists owing to the lack of specific features. The final diagnosis relies on molecular assays. Patients with advanced disease may benefit from TRK inhibitor treatment.

The diagnostic utility of cytology specimen in a case of EWSR1::NFATC2 sarcoma.

EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5' single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens.

Spindle cell neoplasms with novel LTK fusion - Expanding the spectrum of kinase fusion-positive soft tissue tumors.

AIMS: Kinase fusion-positive soft tissue tumors represent an emerging, molecularly defined group of mesenchymal tumors with a wide morphologic spectrum and diverse activating kinases. Here, we present two cases of soft tissue tumors with novel LTK fusions. METHODS AND RESULTS: Both cases presented as acral skin nodules (big toe and middle finger) in pediatric patients (17-year-old girl and 2-year-old boy). The tumors measured 2 and 3 cm in greatest dimension. Histologically, both cases exhibited bland-looking spindle cells infiltrating adipose tissue and accompanied by collagenous stroma. One case additionally displayed perivascular hyalinization and band-like stromal collagen. Both cases exhibited focal S100 staining, and one case had patchy coexpression of CD34. Targeted RNA-seq revealed the presence of novel in-frame MYH9::LTK and MYH10::LTK fusions, resulting in upregulation of LTK expression. Of interest, DNA methylation-based unsupervised clustering analysis in one case showed that the tumor clustered with dermatofibrosarcoma protuberans (DFSP). One tumor was excised with amputation with no local recurrence or distant metastasis at 18-month follow-up. The other case was initially marginally excised with local recurrence after one year, followed by wide local excision, with no evidence of disease at 10 years of follow-up. CONCLUSIONS: This is the first reported case series of soft tissue tumors harboring LTK fusion, expanding the molecular landscape of soft tissue tumors driven by activating kinase fusions. Furthermore, studies involving a larger number of cases and integrated genomic analyses will be warranted to fully elucidate the pathogenesis and classification of these tumors.

Transforming Growth Factor Beta and Alveolar Rhabdomyosarcoma: A Challenge of Tumor Differentiation and Chemotherapy Response.

Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-ß). This overexpression of TGF-ß1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-ß also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-ß in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-ß1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future.

Novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and aggressive presentation.

Childhood melanoma is a rare and biologically heterogeneous pediatric malignancy. The differential diagnosis of pediatric melanoma is usually broad, including a wide variety of spindle cell or epithelioid neoplasms. Different molecular alterations affecting the MAPK and PI3K/AKT/mTOR pathways, tumor suppressor genes, and telomerase reactivation have been implicated in melanoma tumorigenesis and progression. Here, we report a novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and an aggressive clinical course.

FLI1 induces erythroleukemia through opposing effects on UBASH3A and UBASH3B expression.

BACKGROUND: FLI1 is an oncogenic transcription factor that promotes diverse malignancies through mechanisms that are not fully understood. Herein, FLI1 is shown to regulate the expression of Ubiquitin Associated and SH3 Domain Containing A/B (UBASH3A/B) genes. UBASH3B and UBASH3A are found to act as an oncogene and tumor suppressor, respectively, and their combined effect determines erythroleukemia progression downstream of FLI1. METHODS: Promoter analysis combined with luciferase assays and chromatin immunoprecipitation (ChIP) analysis were applied on the UBASH3A/B promoters. RNAseq analysis combined with bioinformatic was used to determine the effect of knocking-down UBASH3A and UBASH3B in leukemic cells. Downstream targets of UBASH3A/B were inhibited in leukemic cells either via lentivirus-shRNAs or small molecule inhibitors. Western blotting and RT-qPCR were used to determine transcription levels, MTT assays to assess proliferation rate, and flow cytometry to examine apoptotic index. RESULTS: Knockdown of FLI1 in erythroleukemic cells identified the UBASH3A/B genes as potential downstream targets. Herein, we show that FLI1 directly binds to the UBASH3B promoter, leading to its activation and leukemic cell proliferation. In contrast, FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby antagonizing leukemic growth. These results suggest oncogenic and tumor suppressor roles for UBASH3B and UBASH3A in erythroleukemia, respectively. Mechanistically, we show that UBASH3B indirectly inhibits AP1 (FOS and JUN) expression, and that its loss leads to inhibition of apoptosis and acceleration of proliferation. UBASH3B also positively regulates the SYK gene expression and its inhibition suppresses leukemia progression. High expression of UBASH3B in diverse tumors was associated with worse prognosis. In contrast, UBASH3A knockdown in erythroleukemic cells increased proliferation; and this was associated with a dramatic induction of the HSP70 gene, HSPA1B. Accordingly, knockdown of HSPA1B in erythroleukemia cells significantly accelerated leukemic cell proliferation. Accordingly, overexpression of UBASH3A in different cancers was predominantly associated with good prognosis. These results suggest for the first time that UBASH3A plays a tumor suppressor role in part through activation of HSPA1B. CONCLUSIONS: FLI1 promotes erythroleukemia progression in part by modulating expression of the oncogenic UBASH3B and tumor suppressor UBASH3A.

Impact of AML1/ETO Fusion on the Efficacy of Venetoclax Plus Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia.

BACKGROUND: AML1/ETO fusion confers favorable prognosis in acute myeloid leukemia (AML) treated with intensive chemotherapy (IC). However, the impact of AML1/ETO fusion on the efficacy of venetoclax in the treatment of AML is unclear. OBJECTIVE: The aim of this study was to evaluate the efficacy of venetoclax plus hypomethylating agents (VEN/HMAs) in patients with AML1/ETO-positive AML. PATIENTS AND METHODS: Patients with newly diagnosed AML in two centers were reviewed and divided into three cohorts: AML1/ETO-positive AML treated with frontline VEN/HMA (Cohort A), AML1/ETO-negative AML treated with frontline VEN/HMA (Cohort B), or AML1/ETO-positive AML treated with frontline IC (Cohort C). The response and survival were compared between the cohorts. RESULTS: A total of 260 patients were included in the study. Patients in Cohort A had a significantly lower overall response rate (ORR) than patients in Cohort B (40.9% vs 71.2%, p = 0.005). The median event-free survival (EFS) in Cohort A and Cohort B was 2.7 months and 7.7 months, respectively, with no significant difference. The ORR and median EFS in Cohort C were 80.8% and 14.9 months, respectively, which were significantly superior to those in Cohort A, and the advantages remained significant after propensity score matching. ORR and EFS in KIT-mutated patients with AML1/ETO-positive AML receiving VEN/HMA were much inferior to those in KIT wild-type patients (ORR 0.0% vs 81.8%, p = 0.001; EFS 1.2 months vs not reached, p < 0.001). CONCLUSIONS: Newly diagnosed AML patients with AML1/ETO fusion had a poor response to frontline VEN/HMA treatment. When determining induction therapy for patients with AML1/ETO-positive AML, IC should be preferred over VEN/HM.

A Comparison of Clear Cell Sarcoma to Jaw and Salivary Tumors Bearing EWS Fusions.

OBJECTIVE: To review tumors identified as "clear cell sarcoma" in order to determine similarities to the rare EWS fusion positive jaw and salivary gland tumors clear cell odontogenic carcinoma (CCOC) and clear cell carcinoma of the salivary gland (CCC). METHODS: PubMed was used to collect all reports of clear cell sarcoma (CCS). Search parameters were "clear cell sarcoma" and "CCS." References in the publications were screened and cross-referenced. Data extracted included demographic characteristics, presenting signs and symptoms, radiographic findings, histological and immunohistochemical features and known molecular/genetic aberrations. RESULTS: Clear cell sarcoma has several similarities to CCOC and CCC. All three tumor types have similar histologic appearances including the presence of clear cells, as well as similar genetic profiles in that all harbor an EWSR1-CREB family fusions. Additionally, these tumors appear in soft tissue as well as bone, and can have a prolonged clinical course. CCS can appear anywhere in the body, including the head and neck region. All three tumors appear to have a predilection to women, although CCS may have a slight younger age of onset as compared to CCOC and CCC (3rd vs 5th decade of life, respectively). CONCLUSION: Gaining a better understanding of the similarities and differences between these three tumors may lead to a better understanding of each one.

CRISPR-Cas9-Mediated Bioluminescent Tagging of Endogenous Proteins by Fluorescent Protein-Assisted Cell Sorting.

Oncogenic fusion genes are attractive therapeutic targets because of their tumor-specific expression and central "driver" roles in various human cancers. However, oncogenic fusions involving transcription factors such as PAX3-FOXO1 in alveolar fusion gene-positive rhabdomyosarcoma (FP-RMS) have been difficult to inhibit due to the apparent lack of tractable drug-like binding sites comparable to that recognized by Gleevec (imatinib mesylate) on the BCR-ABL1 tyrosine kinase fusion protein. Toward the identification of novel small molecules that selectively target PAX3-FOXO1, we used CRISPR-Cas9-mediated knock-in to append the pro-luminescent HiBiT tag onto the carboxy terminus of the endogenous PAX3-FOXO1 fusion protein in two human FP-RMS cell lines (RH4 and SCMC). HiBiT is an 11-amino acid peptide derived from the NanoLuc luciferase that produces a luminescence signal which is ~100-fold brighter than firefly or Renilla luciferases through high-affinity binding to a complementary NanoLuc peptide fragment called LgBiT. To facilitate single-cell clonal isolation of knock-ins, the homology-directed repair template encoding HiBiT was followed by a P2A self-cleaving peptide for coexpression of an mCherry fluorescent protein as a fluorescence-activated cell sorter (FACS)-selectable marker. HiBiT tagging thus allows highly sensitive luminescence detection of endogenous PAX3-FOXO1 levels permitting quantitative high-throughput screening of large compound libraries for the discovery of PAX3-FOXO1 inhibitors and degraders.

A recurrent NTRK1 tyrosine kinase domain mutation pair is characteristic in a subset of dedifferentiated liposarcomas.

INTRODUCTION: Dedifferentiated liposarcoma (DDLPS) is a common form of liposarcoma with challenging treatment modalities. Pan-TRK immunopositivity can be often observed without NTRK gene fusion in soft tissue sarcomas with myogenic differentiation. Expression and the role of NTRK in DDLPS are under-studied. We sought to identify activating mutations of the NTRK genes. MATERIALS AND METHODS: 131 DDLPS patients were selected for pan-TRK immunohistochemistry and positive cases were analyzed by Sanger sequencing for NTRK1, NTRK2 and NTRK3 genes. Functional assays were performed using a lentiviral transduction system to study the effect of NTRK variants in fibroblast, immortalized fibroblast, and dedifferentiated liposarcoma cell lines. RESULTS: Out of the 131 DDLPS cases, 75 immunohistochemical staining positive cases, 46 were successfully Sanger sequenced. A recurrent somatic mutation pair in cis position (NGS) of the NTRK1 c.1810C>T (p.H604Y) and c.1838G>T (p.G613V) was identified in six cases (13%) that have never been reported in DDLPS. NTRK fusions were excluded in all six cases by FISH and NGS. The phospho-AKT immunopositivity among the six mutated cases suggested downstream activation of the NTRK signaling pathway. Functional assays showed no transforming effects, but resistance to first- and second-line TRK inhibitors of the p.G613V and p.H604Y variant. CONCLUSIONS: We detected (de novo/somatic) missense mutation variants in cis position of the NTRK1 gene in a subset of DDLPS indicating modifying mutations that may contribute to tumorigenesis in a subset of DDLPS. These variants beget resistance to TRK inhibitors indicating an interesting biomarker for other studies with TRK inhibitors.

Clinical Analysis of Pediatric Acute Megakaryocytic Leukemia With CBFA2T3-GLIS2 Fusion Gene.

CBFA2T3-GLIS2 is the most frequent chimeric oncogene identified to date in non-Down syndrome acute megakaryocytic leukemia (AMKL), which is associated with extremely poor clinical outcome. The presence of this fusion gene is associated with resistance to high-intensity chemotherapy, including hematopoietic stem cell transplantation (HSCT), and a high cumulative incidence of relapse frequency. The clinical features and clinical effects of China Children's Leukemia Group-acute myeloid leukemia (AML) 2015/2019 regimens and haploidentical HSCT (haplo-HSCT) for treatment of 6 children harboring the CBFA2T3-GLIS2 fusion gene between January 2019 and December 2021 were retrospectively analyzed. The 6 patients included 4 boys and 2 girls with a median disease-onset age of 19.5 months (range: 6-67 mo) who were diagnosed with AMKL. Flow cytometry demonstrated CD41a, CD42b, and CD56 expression and lack of HLA-DR expression in all 6 patients. All the children were negative for common leukemia fusion genes by reverse transcription polymerase chain reaction, but positive for the CBFA2T3-GLIS2 fusion gene by next-generation sequencing and RNA sequencing. All patients received chemotherapy according to China Children's Leukemia Group-AML 2015/2019 regimens, and 4 achieved complete remission. Four children underwent haplo-HSCT with posttransplant cyclophosphamide-based conditioning; 3 had minimal residual disease negative (minimal residual disease <0.1%) confirmed by flow cytometry at the end of the follow-up, with the remaining patient experiencing relapse at 12 months after transplantation. Transcriptome RNA sequencing is required for the detection of the CBFA2T3-GLIS2 fusion gene and for proper risk-based allocation of pediatric patients with AML in future clinical strategies. Haplo-HSCT with posttransplant cyclophosphamide-based conditioning may improve survival in children with AMKL harboring the fusion gene.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Mitoxantrone and abacavir: An ALK protein-targeted in silico proposal for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a type of lung cancer associated with translocation of the EML4 and ALK genes on the short arm of chromosome 2. This leads to the development of an aberrant protein kinase with a deregulated catalytic domain, the cdALK+. Currently, different ALK inhibitors (iALKs) have been proposed to treat ALK+ NSCLC patients. However, the recent resistance to iALKs stimulates the exploration of new iALKs for NSCLC. Here, we describe an in silico approach to finding FDA-approved drugs that can be used by pharmacological repositioning as iALK. We used homology modelling to obtain a structural model of cdALK+ protein and then performed molecular docking and molecular dynamics of the complex cdALK+-iALKs to generate the pharmacophore model. The pharmacophore was used to identify potential iALKs from FDA-approved drugs library by ligand-based virtual screening. Four pharmacophores with different atomistic characteristics were generated, resulting in six drugs that satisfied the proposed atomistic positions and coupled at the ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best interaction energies with 228.29, 165.40 and 133.48 KJoul/mol respectively. In addition, the special literature proposed these drugs for other types of diseases due to pharmacological repositioning. This study proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover, we identified pharmacophores sites that can be tested with other pharmacological libraries.