The role of mutations in epigenetic regulators in myeloid malignancies

Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.     

Listeriosis in hematological malignancies: report of two cases

Listeriosis occurred in two patients with hematological malignancies, one with adult T-cell leukemia (ATL) (Case 1) and the other with chronic granulocytic leukemia (CGL) (Case 2). In Case 1, listeriosis was the initial manifestation of ATL, while it occurred in Case 2 after prolonged treatment with an alkylating agent and splenic irradiation. In both cases, depressed cell-mediated immunity was considered to be responsible for the listeriosis. Experience with the present two cases has indicated that listeriosis can be an initial manifestation of ATL, and the combination of an alkylating agent and splenic irradiation may increase the risk of listeriosis in patients with CGL.     

fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies

Patients with neurofibromatosis type 1 (nf1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although ¹⁸F-fluorodeoxyglucose positron-emission tomography (fdg-pet) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg-pet characteristics for more rare tumours have been poorly described in children with nf1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf1, fdg-pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.     

Genetics of myeloid malignancies: pathogenetic and clinical implications.

Myeloid malignancies are clonal disorders that are characterized by acquired somatic mutation in hematopoietic progenitors. Recent advances in our understanding of the genetic basis of myeloid malignancies have provided important insights into the pathogenesis of acute myeloid leukemia (AML) and myeloproliferative diseases (MPD) and have led to the development of novel therapeutic approaches. In this review, we describe our current state of understanding of the genetic basis of AML and MPD, with a specific focus on pathogenetic and therapeutic significance. Specific examples discussed include RAS mutations, KIT mutations, FLT3 mutations, and core binding factor rearrangements in AML, and JAK2 mutations in polycythemia vera, essential thrombocytosis, and chronic idiopathic myelofibrosis.     

Trametinib in the treatment of multiple malignancies harboring MEK1 mutations

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.     

G-CSF-induced remission in two cases of acute myeloid leukemia

We report on two elderly patients with newly diagnosed acute myeloid leukemia (AML) who were treated in palliative intention because of comorbidities and intermediate or poor risk cytogenetics. Both received G-CSF to reduce the risk of infection related to neutropenia. Interestingly, one patient achieved a full hematological remission and the other a peripheral remission with dramatic reduction of the bone marrow blast count. Although a direct therapeutic effect of myeloid growth factors seems to be unusual in AML, the use of G-CSF or GM-CSF may be recommended in patients such as elderly patients who are not suited for intensive chemotherapy.     

Mutations of c-Cbl in myeloid malignancies

Next generation sequencing has shown the frequent occurrence of point mutations in the ubiquitin E3 ligase c-Cbl in myeloid malignancies. Mouse models revealed a causal contribution of c-Cbl for the onset of such neoplasms. The point mutations typically cluster in the linker region and RING finger domain and affect both alleles by acquired uniparental disomy. The fast progress in the detection of c-Cbl mutations is contrasted by our scarce knowledge on their functional consequences. The c-Cbl protein displays several enzymatic functions by promoting the attachment of differentially composed ubiquitin chains and of the ubiquitin-like protein NEDD8 to its target proteins. In addition, c-Cbl functions as an adapter protein and undergoes phosphorylation-dependent inducible conformation changes. Studies on the impact of c-Cbl mutations on its functions as a dynamic and versatile adapter protein, its interactomes and on its various enzymatic activities are now important to allow the identification of druggable targets within the c-Cbl signaling network.     

Multiple primary malignancies: a report of two cases

The diagnosis of multiple primary malignancies （MPMs） in a patient has been reported rather frequently during the past decade. Here we present two cases with three synchronous primary malignant tumors. The first patient is a 66-year-old male with synchronous colorectal cancer, renal cell carcinoma （RCC） and non-small cell lung cancer （NSCLC）. The second patient is a 64-year-old female with breast cancer, transitional cell carcinoma of the ureter and endometrial cancer. MPMs seem to be diagnosed in a higher incidence than that predicted only by the influence of hazard and, whenever found, they raise questions regarding not only possible common etiologic factors or same pathogenetic mechanisms but also they cause a lot of troubles to both clinicians and patients because the therapeutic options usually become limited.     

Multiple primary malignancies in patients with alcoholic liver disease. A report of two cases.

Two patients, each with three primary malignant neoplasms are presented. In an effort to identify a possible common denominator of induction of these tumors, it was found that both patients were alcoholics with liver disease, and that both had impaired delayed hypersensitivity reactions. The possibility of an increased susceptibility to cancer among alcoholics with liver disease is noted and the need for careful follow-up of these patients is suggested.     

Primary myeloid sarcoma of the gynecologic tract: a report of two cases progressing to acute myeloid leukemia

Primary gynecologic myeloid sarcomas are rare, and their diagnosis is often difficult. Differential diagnosis includes lymphomas and carcinomas of the gynecologic tract. We report the clinical, morphological, immunohistochemical and cytogenetic features of two cases of chloromas of the female genital tract, which progressed to acute myeloid leukemia in spite of aggressive therapy.