Malignant Transformation Research Articles

Polyclonal-to-monoclonal transition in colorectal precancerous evolution.

Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1-3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent celllineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.

Clinical and Dermoscopic Characteristics of Cutaneous Chondroid Syringoma: A Systematic Review

Introduction: Cutaneous chondroid syringoma (CS) is a rare benign mixed skin tumor originating from sweat glands. Despite its rarity, accurate diagnosis and management are crucial due to its potential for malignant transformation. Objective: This study aims to provide comprehensive insights into the main features of cutaneous CS, encompassing its epidemiology, clinical presentation, and particularly, dermoscopic findings. Methods: A systematic review was conducted to identify relevant literature on CS up to November 2023. Data extraction included clinical and histopathological characteristics from case reports and small case series. Results: The systematic review identified 347 unique CS cases, predominantly benign. Clinical features included a predilection for the head and neck region, with variations in morphology observed. Dermoscopic patterns, although limited, revealed recurrent features aiding diagnosis. Malignant CS cases constituted a notable subset, exhibiting distinct clinical and histopathological features. Conclusion: Cutaneous chondroid syringoma presents with characteristic clinical and histopathological features, necessitating comprehensive diagnostic approaches. Dermoscopy emerges as a valuable tool, although further research is needed to establish definitive patterns. Treatment primarily involves wide local excision, with collaboration among clinicians essential for optimal management. Future studies are warranted to address existing knowledge gaps and enhance understanding of this rare skin neoplasm.

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.

A rare case of a pleomorphic adenoma of the submandibular gland

We report the case of a 27-year-old female with a painless slowly growing mass that had developed over 2 years in the right submandibular region. Physical examination revealed a firm painless submandibular mass. Fine-needle aspiration and computed tomography (CT) scan concluded a pleomorphic adenoma of the submandibular gland. The patient underwent a right total submandibular sialoadenectomy. Histopathological examination confirmed the diagnosis of pleomorphic adenoma arising from the submandibular gland. Transient palsy of the marginal mandibular division of the facial nerve was noted post-operatively, which recovered with supportive management. Pleomorphic adenoma of the submandibular gland represents a diagnostic and therapeutic dilemma in young adults. Preoperative evaluation, including MRI/CT scan and fine-needle aspiration, is recommended in all cases. Total submandibular sialoadenectomy is the standard recommended treatment to minimise recurrences and avoid malignant transformation.

Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes

Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.

Myoid Hamartoma of the Breast With HMGA2 Rearrangement and Associated In-Situ and Invasive Carcinoma: Case Report and Review of Literature.

Myoid hamartoma of the breast is an uncommon benign breast neoplasm. We describe an unusual example of an in-situ and invasive carcinoma arising in a myoid hamartoma. We also describe the unique molecular findings in the myoid hamartoma and review the pertinent literature. In radiology studies, the mammogram showed increased density/attenuation, and the ultrasound revealed a change in the overall echogenicity with hyperechoic and anechoic areas. The stromal compartment contained smooth muscle bundles and adipose tissue on microscopic examination. The stromal cells showed HMGA2 gene rearrangement by fluorescence in-situ hybridization analysis and overexpression of HMGA2 by immunohistochemistry. The breast myoid hamartoma is likely underpinned by HMGA2 gene rearrangement and HMGA2 protein overexpression, which can be used as an ancillary test to diagnose this rare breast lesion. Although most myoid hamartomas have a benign clinical course, the likelihood of malignant transformation should always be considered.

Poroid Hidradenoma: A Rare Eccrine Tumor in an Unusual Location

Poroid hidradenoma (PH) is a rare benign neoplasm of eccrine origin, typically located within the dermis. It most commonly affects individuals in the sixth and seventh decades of life, though it can present at any age. The head, neck, and trunk are typical locations. This case report details a 26-year-old male with a large PH on the right hip, an atypical location. The lesion began as a small, painful nodule and progressively grew over 18 months. Initial treatment, suspected to be for an abscess, was unsuccessful. A dermatological evaluation revealed a 7 x 8 cm exophytic, ulcerated mass, and biopsy confirmed the diagnosis of PH. Histopathological analysis showed solid and cystic components, with poroid cells identified. Immunohistochemistry was positive for markers such as CEA, CK-7, and p63, which are consistent with this tumor type. Following the confirmed diagnosis, complete surgical excision was performed, and the patient remains asymptomatic with no signs of recurrence. Poroid hidradenoma is characterized by both poroid and cuticular cells, and although it is generally benign, malignant transformation has been reported in less than 1% of cases. Therefore, complete excision is recommended to reduce the risk of recurrence and malignancy. This case highlights the importance of early diagnosis and appropriate management of PH, including long-term follow-up to ensure the absence of recurrence.

Anti-VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis.

Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of Hif1a and Vegfa along with hypoxic status and found that OED exhibited increased Vegfa expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Role of CLDN18.2 in Gastric Cancer Prognosis: A Systematic Review and Meta-Analysis

Background Gastric cancer (GC) is a major global cause of cancer mortality, with a median overall survival of just 12 months. CLDN18.2, a specific isoform of Claudin18 normally expressed in the gastric mucosa, has emerged as a potential therapeutic target and prognostic biomarker due to its exposure on the surface of tumor cells following malignant transformation. This exposure allows CLDN18.2's extracellular loops to bind monoclonal antibodies, presenting new opportunities for targeted therapy and improved prognostic assessment. Methods A comprehensive search of PubMed, EMBASE, Cochrane Library and Web of Science databases was conducted for studies that addressed the correlation of CLDN18.2 with: (1) Progression-free survival (PFS), and (2) Overall Survival (OS). Hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. Heterogeneity was examined with I2 statistics. P values of ≤ 0.05 were considered statistically significant. Statistical analyses were performed using RStudio, version 4.2.3. Results A total of 15 studies encompassing a total of 4,085 patients were included. There were 2,691 (65.8%) male, and 1,394 (34.2%) female patients. In the histologic GC analysis, there were 1,582 (38.7%) patients that had intestinal type and 1,280 (31.3%) with diffuse type. Patients with CLDN18.2 negative status exhibited a non-significant trend towards prolonged PFS (HR: 1.25; 95% CI: 0.98-1.61; p = 0.07; I2=18%) and a significant prolonged OS (HR: 1.20; 95% CI: 1.07-1.34; p < 0.01; I2=37%) when compared to CLDN18.2-positive patients. Conclusion Our findings establish CLDN18.2 as a robust negative prognostic indicator for overall survival in GC patients. While its impact on PFS was not statistically significant, the association with OS suggests CLDN18.2 may serve as a marker for complex biological processes underlying tumor advancement.

A clinical case of congenital cystic adenomatous malformation of the lung type II

Cystic adenomatous malformation of the lung is a rather rare congenital malformation of the respiratory system characterized by the formation of cysts of various diameters, manifesting as respiratory distress syndrome in the postnatal period, and frequent respiratory infections. This pathology has several developmental variants, including malignant transformation and regression, and may also be associated with other developmental anomalies. The final diagnosis is established on the basis of histologic features. Clinically manifest forms require surgical intervention in the early postpartum period. The treatment of asymptomatic cases remains controversial. Some specialists recommend a nonoperative approach with prolonged clinical and radiologic follow-up, while others advocate prophylactic surgical resection. In this article, we consider a clinical case of a 4-month-old child who, since the age of 2 months, had this pathology accompanied by frequent episodes of respiratory infections, complicated by bronchitis, bronchial obstruction syndrome, respiratory failure of varying degrees and once - up to the development of out-of-hospital bilateral polysegmental pneumonia, which required the prescription of multicomponent pharmacotherapy. Computerized tomography of the chest organs was crucial in diagnosing the pathology, which revealed cysts of the upper lobe of the right lung.

Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

Stromal softness confines pancreatic cancer growth through lysosomal-cathepsin mediated YAP1 degradation

The progression and malignancy of many tumors are associated with increased tissue stiffness. Conversely, the oncogenically transformed cells can be confined in soft stroma. Yet, the underlying mechanisms by which soft matrix confines tumorigenesis and metastasis remain elusive. Here, we show that pancreatic cancer cells are suppressed in the soft extracellular matrix, which is associated with YAP1 degradation through autophagic-lysosomal pathway rather than Hippo signal mediated proteasome pathway. In the soft stroma, PTEN is upregulated and activated, which consequently promotes lysosomal biogenesis, leading to the activation of cysteine-cathepsins for YAP1 degradation. In vitro, purified cathepsin L can directly digest YAP1 under acidic conditions. Lysosomal stress, either caused by chloroquine or overexpression of cystatin A/B, results in YAP1 accumulation and malignant transformation. Likewise, liver fibrosis induced stiffness can promote malignant potential in mice. Clinical data show that down-regulation of lysosomal biogenesis is associated with pancreatic fibrosis and stiffness, YAP1 accumulation, and poor prognosis in PDAC patients. Together, our findings suggest that soft stroma triggers lysosomal flux-mediated YAP1 degradation and induces cancer cell dormancy.Graphical

Stemness in solid malignancies: coping with immune attack.

Immunotherapy has become a key new pillar of cancer treatment, and this has sparked interest in understanding mechanisms of cancer immune evasion. It has long been appreciated that cancers are constituted by heterogeneous populations of tumour cells. This feature is often fuelled by specialized cells that have molecular programs resembling tissue stem cells. Although these cancer stem cells (CSCs) have capacity for unlimited self-renewal and differentiation, it is increasingly evident that some CSCs are capable of achieving remarkable immune resistance. Given that most immunotherapy regiments have overlooked CSC-specific immune-evasive mechanisms, many current treatment strategies often lead to cancer relapse. This Review focuses on advancements in understanding how CSCs in solid tumours achieve their unique immune-evasive properties, enabling them to drive tumour regrowth. Moreover, as cancers often arise from tissue stem cells that acquired oncogenic mutations, we discuss how tissue stem cells undergoing malignant transformation activate intrinsic immune-evasive mechanisms and establish close interactions with suppressive immune cells to escape immune surveillance. In addition, we summarize how in advanced disease stages, CSCs often hijack features of normal stem cells to resist antitumour immunity. Finally, we provide insights in how to design a new generation of cancer immunotherapies to ensure elimination of CSCs.

An extraordinary case of Buschke–Lowenstein tumor: multiple localization, malignant transformation, and clinical insights—a case presentation and literature review

BackgroundBuschke–Lowenstein (B–L) tumors are rare, aggressive warty lesions that can grow to enormous sizes and have a risk of malignant transformation despite their benign histology. These tumors are primarily caused by HPV types 6 and 11, with additional risk factors, including immunodeficiency, multiple sexual partners, poor hygiene, and a history of other genital infections. The typical treatments include topical medications, cryotherapy, chemotherapy, radiotherapy, and surgery. Surgery is considered the gold standard, particularly for extensive and infiltrative lesions, as demonstrated in our case.Case presentationWe report a case of a male patient with perianal and penopubic B–L tumors, who had multiple sexual partners and no history of homosexual relationships, presenting with refractory classic condyloma. The perianal tumor exhibited malignant transformation, while the penopubic tumor remained histopathologically benign. Upon admission, the patient showed unusual biochemical blood results, including hypercalcemia and anemia of chronic illness. The operation and postoperative period were managed by a multidisciplinary team. The patient was satisfied with both the cosmetic and functional outcomes. Histopathological examination confirmed the suprapubic lesion as a B–L tumor, whereas the perianal specimen revealed a small focus of squamous cell carcinoma arising from a B–L tumor.ConclusionsWith an experienced multidisciplinary team, excision of the tumor is still the standard treatment for BL tumor. Achieving a negative surgical margin for any SCC foci is of utmost importance to prevent recurrence. Close and careful follow-up is essential due to the high recurrence rate associated with these tumors. Further research is needed to clarify existing controversies and to enrich the literature on this rare phenomenon.

Squamous Cell Carcinoma Arising in a Squamous Odontogenic Tumor of the Maxilla: Case Report and Review of the Literature.

Squamous odontogenic tumor (SOT) is an exceedingly rare, benign epithelial odontogenic tumor showing squamous differentiation. It is composed of variably sized and shaped islands of cytologically bland, mature squamous epithelium within a fibrous stroma. In this report, we present a rare transformation of a squamous odontogenic tumor (SOT) of the maxilla into a well-differentiated squamous cell carcinoma (SCC) with involvement of the pterygoid plates. To the best of our knowledge, only two cases of malignant transformation of SOT has been reported in the literature. Herein, we seek to report this extremely rare occurrence to raise awareness of oral and maxillofacial surgeons and pathologists of this unusual, but serious event and perform a literature review of squamous odontogenic tumors.

Salivary Gland Tumours in Children and Adolescents-A Study in Shaheed Monsur Ali Medical College &amp; Hospital, Uttara, Dhaka, Bangladesh

Introduction: Salivary gland carcinomas (SGCs) are rare neoplasms in adults, but are exceedingly infrequent in children, with a reported annual incidence of 0.8–1.4 per million populations under 20 years old. Like other pediatric very rare tumors, SGCs in children and adolescents often present diagnostic and therapeutic challenges for pathologists, surgeons, and pediatric oncologists. Objective: To assess the salivary gland tumours in children and adolescents. Methods: A cross-sectional observational study was carried out at Dept. of ENT, Shaheed Monsur Ali Medical College &amp; Hospital, Uttara, Dhaka, Bangladesh from January to June 2023. Total 60 patients included in our study. Our pre-operative clinical diagnoses were based on size, shape, mobility, fixity of the tumour to the underlying structures, ulceration of overlying skin, involvement of facial nerve by its malignant transformation and fine needle aspiration cytology. All patients, or their guardians, gave their informed consent for data collection within the national rare tumour group and analysis. Results: Total sixty (60) cases of salivary gland tumours were available for our study. Out of 55% were male and 45% were female patients. Incidence of tumours is highest in the age group of 41-50 with 13 cases (21.6% of the total). The least affected age group was the 0-10 group with only one patient (3.3%). Women accounted for 16 cases of the total 33 benign neoplasias (55% of the total). Of the 33 benign tumour, 18 were in males (54.5% of all benign tumours) and 15 were in females (45.5%). Total 60 operated cases). Of these, 32 were pleomorphic adenomas (53.3%) and 1 was an adenolymphoma (1.6%). the total number of malignant tumours confirmed by HPE were 27 (45%). Of these, most numerous was adenoid cystic carcinoma in 8 cases (13.3%). squamous cell carcinoma and muco epidermoid carcinoma were found in 6 cases each (10%). There were 4 and 3 cases of adenocarcinoma (6.6%) and acinic cell carcinoma (5%) respectively. The parotid glands were also the sole location for the 3 acinic cell carcinomas. No tumours were found in the sublingual gland. The majority of the tumours found in the parotid gland were benign tumours, mainly pleomorphic adenomas with 24 cases (75% of the total parotid tumours). Conclusions: The tumours were equally distributed between males and females. The tumours were most commonly found in the third to fifth decades of life. The most common benign tumour and the most common tumour overall was pleomorphic adenoma making up 54.5% of all tumours. Surgical excision was the most commonly done treatment. The most commonly done surgical procedure was superficial parotidectomy.

Malignant transformation in giant sebaceous cysts: Uncommon but not impossible.

Malignant transformation in giant sebaceous cysts: Uncommon but not impossible.

Adhesive lipophilic gels delivering rapamycin prevent oral leukoplakia from malignant transformation

Oral leukoplakia (OLK) is the most emblematic oral potentially malignant disorder that may precede the diagnosis of oral squamous cell carcinoma (OSCC) and has an overall malignant transformation rate of 9.8 %. Early intervention is crucial to reduce the malignant transformation rate from OLK to OSCC but the lack of effective local pharmaceutical preparations poses a challenge to clinical management. Rapamycin is speculated to prevent OLK from carcinogenesis and its inherent lipophilicity facilitates its penetration into stratum corneum. Nevertheless, hydrophilic hydrogels frequently encounter challenges when attempting to deliver lipophilic drugs. Furthermore, the oral cavity presents a complex environment defined by oral motor functions, saliva secretion cycles, dynamic fluctuations, and protective barriers comprising mucus and lipid layers. Consequently, addressing issues of muco-penetration and muco-adhesion is imperative for developing an effective drug delivery system aiming at delivering rapamycin to target oral potentially malignant disorders.Here, a dual-function hydrogel drug delivery system integrating adhesion and lipophilicity was successfully developed based on polyvinyl alcohol (PVA) and dioleoyl phosphatidylglycerol (DOPG) via dynamic boronic ester bonds. Rheological experiments based on orthogonal design revealed that PVA-DOPG hydrogels exhibited ideal adhesive strength (around 6 kPa) and could adhere to various surfaces in both dry and wet conditions. PVA-DOPG hydrogels also significantly promoted lipophilic molecules’ penetration into stratum corneum (integrated fluorescence density of 6.95 ± 0.52 × 106 and mean fluorescence depth of 0.96 ± 0.07 mm) of ex-vivo porcine buccal mucosa (p < 0.001). Furthermore, PVA-DOPG hydrogels incorporating rapamycin inhibited malignant transformation of OLK mouse model induced by 4-Nitroquinoline N-oxide (4-NQO), distinct improvements in survival (the neoplasm incidence density at the 40th day is 0.0091) (p < 0.05), decrease in neoplasm incidence density of 36.36 % and inhibition rate in neoplasm volume of 75.04 ± 33.67 % have been demonstrated, suggesting the hydrogels were valuable candidates for potential applications in the management of OLK.

Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression.

Hematopoietic stem cells (HSCs) drive cellular turnover in the hematopoietic system by balancing self-renewal and differentiation. In the adult bone marrow (BM), these cells are regulated by a complex cellular microenvironment known as "niche," which involves dynamic interactions between diverse cellular and non-cellular elements. During blood cell maturation, lineage branching is guided by clusters of genes that interact or counteract each other, forming complex networks of lineage-specific transcription factors. Disruptions in these networks can lead to obstacles in differentiation, lineage reprogramming, and ultimately malignant transformation, including acute myeloid leukemia (AML). Zinc Finger Protein 521 (Znf521/Zfp521), a conserved transcription factor enriched in HSCs in both human and murine hematopoiesis, plays a pivotal role in regulating HSC self-renewal and differentiation. Its enforced expression preserves progenitor cell activity, while inhibition promotes differentiation toward the lymphoid and myeloid lineages. Transcriptomic analysis of human AML patient samples has revealed upregulation of ZNF521 in AMLs with the t(9;11) fusion gene MLL-AF9. In vitro studies have shown that ZNF521 collaborates with MLL-AF9 to enhance the growth of transformed leukemic cells, increase colony formation, and activate MLL target genes. Conversely, inhibition of ZNF521 using short-hairpin RNA (shRNA) results in decreased leukemia proliferation, reduced colony formation, and induction of cell cycle arrest in MLL-rearranged AML cell lines. In vivo experiments have demonstrated that mZFP521-deficient mice transduced with MLL-AF9 experience a delay in leukemia development. This review provides an overview of the regulatory network involving ZNF521, which plays a crucial role in controlling both HSC self-renewal and differentiation pathways. Furthermore, we examine the impact of ZNF521 on the leukemic phenotype and consider it a potential marker for MLL-AF9+ AML.

Hereditary multiple exostoses

Hereditary multiple exostoses is a rare congenital condition with autosomal dominant inheritance. It consists of formation of osteocartilaginous exostoses, most commonly from the metaphysis of long bones. Surgery is the main treatment as there is no available medical treatment. Clinical follow-ups with orthopaedic specialists are important, both in childhood and adulthood. In childhood, focus is on managing symptoms and removing symptomatic exostoses, while in adulthood, MRI is performed to rule out malignant transformation, as argued in this review.