Epigenetic dysregulation of ID4 predicts disease progression and treatment outcome in myeloid malignancies

Promoter hypermethylation‐mediated inactivation of ID4 plays a crucial role in the development of solid tumours. This study aimed to investigate ID4 methylation and its clinical relevance in myeloid malignancies. ID4 hypermethylation was associated with higher IPSS scores, but was not an independent prognostic biomarker affecting overall survival (OS) in myelodysplastic syndrome (MDS). However, ID4 hypermethylation correlated with shorter OS and leukaemia‐free survival (LFS) time and acted as an independent risk factor affecting OS in acute myeloid leukaemia (AML). Moreover, ID4 methylation was significantly decreased in the follow‐up paired AML patients who achieved complete remission (CR) after induction therapy. Importantly, ID4 methylation was increased during MDS progression to AML and chronic phase (CP) progression to blast crisis (BC) in chronic myeloid leukaemia (CML). Epigenetic studies showed that ID4 methylation might be one of the mechanisms silencing ID4 expression in myeloid leukaemia. Functional studies in vitro showed that restoration of ID4 expression could inhibit cell proliferation and promote apoptosis in both K562 and HL60 cells. These findings indicate that ID4 acts as a tumour suppressor in myeloid malignancies, and ID4 methylation is a potential biomarker in predicting disease progression and treatment outcome.     

TrkC promotes survival and growth of leukemia cells through Akt-mTOR-Dependent Up-Regulation of PLK-1 and Twist-1

It has been suggested that activation of receptor PTKs is important for leukemogenesis and leukemia cell response to targeted therapy in hematological malignancies including leukemia. PTKs induce activation of the PI3K/Akt/mTOR pathway, which can result in prevention of apoptosis. Here, we describe an important role of the TrkC-associated molecular network in the process of leukemogenesis. TrkC was found to be frequently overexpressed in human leukemia cells and leukemia subtypes. In U937 human leukemia cells, blockade of TrkC using small hairpin RNA (shRNA) specific to TrkC or K562a, a specific inhibitor of TrkC, resulted in a significant decrease in growth and survival of the cells, which was closely associated with reduced mTOR level and Akt activity. In addition, TrkC enhances the survival and proliferation of leukemia, which is correlated with activation of the PI3K/Akt pathway. Moreover, TrkC significantly inhibits apoptosis via induction of the expression of PLK-1 and Twist-1 through activation of AKT/mTor pathway; therefore, it plays a key role in leukemogenesis. These findings reveal an unexpected physiological role for TrkC in the pathogenesis of leukemia and have important implications for understanding various hematological malignancies.     

Thrombotic microangiopathy in oncology – a review

Thrombotic microangiopathy is a syndrome triggered by a wide spectrum of situations, some of which are specific to the Oncology setting. It is characterized by a Coombs-negative microangiopathic haemolytic anemia, thrombocytopenia and organ injury, with characteristic pathological features, resulting from platelet microvascular occlusion.TMA is rare and its cancer-related subset even more so. TMA triggered by drugs is the most common within this group, including classic chemotherapy and the latest targeted therapies. The neoplastic disease itself and hematopoietic stem-cell transplantation could also be potential triggers.Evidence-based medical guidance in the management of cancer-related TMA is scarce and the previous knowledge about primary TMA is valuable to understand the disease mechanisms and the potential treatments.Given the wide spectrum of potential causes for TMA in cancer patients, the aim of this review is to gather the vast information available. For each entity, pathophysiology, clinical features, therapeutic approaches and prognosis will be covered.     

TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity

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Cyclophilin A regulates secretion of tumour-derived extracellular vesicles

Extracellular Vesicles (EVs) are a heterogenous population of particles that play an important role in cell-cell communication in physiological and pathophysiological situations. In this study we reveal that the peptidyl prolyl isomerase Cyclophilin A (CypA) is enriched in cancer-derived EVs from a range of haematopoietic malignancies. CypA-enriched blood cancer EVs were taken up by normal monocytes independent of EV surface trypsin-sensitive proteins and potently stimulated pro-inflammatory MMP9 and IL-6 secretion. Further characterisation revealed that CypA is intravesicular, however, it is not present in all EVs derived from the haematopoietic cells, instead, it is predominantly located in high density EVs with a range of 1.15–1.18 g/ml. Furthermore, loss of CypA expression in haematological cancer cells attenuates high density EV-induced pro-inflammatory MMP9 and IL-6 secretion from monocytes. Mechanistically, we reveal that homozygous loss or siRNA knockdown of CypA expression significantly reduced the secretion of EVs in the range of 100–200 nm from blood cancer cells under normal and hypoxic conditions. Overall, this work reveals a novel role for CypA in cancer cell EV biogenesis.     

Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis

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Aspiration cytodiagnosis of small cell malignancies found in fine needle aspirate (FNA) of the liver: an immunocytochemical study

In this study the features of small cell malignancies found in the liver by fine needle aspiration cytology (FNAC) and immunostains required for a diagnosis and differential diagnosis are presented. The material consisted of 197 fine needle aspirates which were performed under image guidance between January 1982 to October 1999. Of these, 30 were diagnosed as small cell malignancies. The age of patients ranged between 46 and 68 years. The aspirated material was examined using Papanicolaou-stained filter preparations and cell blocks, the latter stained with hematoxylin and eosin and a panel of immunoperoxidase stains. The diagnoses based on a correlation of relevant clinical history, cytohistological findings and immunostaining were: metastatic small cell anaplastic carcinoma of lung (n = 6); neuroendocrine tumour (n = 9); non-Hodgkin's lymphoma (n = 4); well-differentiated cholangiocarcinoma (n = 2); metastatic carcinoma of the prostate (n = 2); metastatic adenocarcinoma (n = 4) and metastatic carcinoma breast (n = 3). This study emphasizes the wide range of neoplasms that enter into the differential diagnosis of small cell malignancies found in the liver and a correlation of clinical, cytohistological and immunostaining findings which seem to be useful in suggesting a diagnosis.     

Protein biomarkers for response to XPO1 inhibition in haematologic malignancies

XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumour and haematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes, not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using haematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision-making in the personalized treatment of cancer patients undergoing treatment with selinexor.     

Extracellular vesicles: Regenerative medicine prospect in hematological malignancies

Extracellular vesicles (EVs) either as endocytic or plasma membrane-emerged vesicles play pivotal role in cell-to-cell communication. Due to the bioactive molecules transformation, lymphoma cell-derived vesicles can alter a recipient cell's function and contribute to signal transduction and drug resistance. These vesicles by acting not only in tumor cells but also in tumor-associated cells have important roles in tumor growth and invasion. On the other hand, the total protein level of circulating exosomes reveals the disease stage, tumor burden, response to therapy, and survival. In residual disease, leukemic blasts are undetectable in the bone marrow by conventional methods but exosomal proteins are elevated significantly. In this manner, new methods for measuring exosomes and exosomal components are required. In this review, we try to reveal the concealed role of EVs in hematological malignancies besides therapeutic potentials.