Konstantinos Zervakis

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

Evidence for regulation of oxidative stress by latent membrane protein 1 oncoprotein in patients with low-grade leukemic B cell lymphoma with latent Epstein - Barr virus infection

Abstract The role of latent Epstein–Barr virus (EBV) infection in the pathogenesis of low-grade B cell non-Hodgkin lymphoma (B-NHL) has not been studied. We therefore investigated the incidence of latent EBV infection in a group of patients with leukemic low-grade B-NHL, as well as the incidence of viral latent membrane protein 1 (LMP1) oncoprotein expression in the same patient group. Furthermore, in an attempt to elucidate the role of this viral oncoprotein in non-EBV-related lymphomas, we correlated the expression of LMP1 with the level of oxidative stress, a parameter related to apoptosis. In the present study we detected lower levels of oxidative stress in the sera of LMP1-positive patients. This possibly implies an anti-apoptotic role of this viral oncoprotein in low-grade B cell lymphomas. However, LMP1 expression status did not affect expression of the major anti-apoptotic gene BCL-2.

An Adult Patient with Systemic Mastocytosis and B-Acute Lymphoblastic Leukemia

Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children.

An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(12;17)(p13;q21)/ZNF384-TAF15

This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(12;17)(p13;q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 and/or CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384/TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy.

Evaluation of the performance of tuberculin skin test and Quantiferon-TB gold in tube test in patients with hematologic malignancies

To cite this article: Panagiotis T. Diamantopoulos, Gerasimos D. Tsilimidos, Konstantinos Zervakis, Katerina Polonyfi, Maria Sofotasiou, Marie-Christine Kyrtsonis, Athanasios Aessopos, Georgios Kyriakakis & Nora A. Viniou (2017): Evaluation of the performance of tuberculin skin test and Quantiferon-TB gold in tube test in patients with hematologic malignancies, Infectious Diseases, DOI: 10.1080/23744235.2017.1280619 To link to this article: http://dx.doi.org/10.1080/23744235.2017.1280619

Staphylococcus aureus meningitis in a patient with mantle cell lymphoma under treatment with ibrutinib

Dear Editor, Spontaneous hematogenous non-surgical staphylococcal meningitis is a rare entity with high mortality. Risk factors for Staphylococcus aureus bacteremia (SAB) include age, HIV infection, hemodialysis, and intravenous drug use (IDU) [1], but the risk of meningitis among patients with SAB is <1% [2], and the only identifiable risk factor for meningitis is IDU. We present a patient with mantle cell lymphoma (MCL) under treatment with ibrutinib that developed meningitis from S. aureus. A 72-year-old man was admitted to the hospital due to confusion, headache, and low-grade fever. The patient had been diagnosed with stage IV MCL 23 months earlier. His medical history was unremarkable except for a chronic mechanical low back pain. After three lines of immunochemotherapy, he had a recurrence and was started on ibrutinib that he had been taking for 5 months till the day of admission. Fifteen days earlier, he had a low back pain exacerbation and was treated with a series of non-steroidal anti-inflammatory drug intramuscular injections. Upon admission, nuchal rigidity was detected. The lumbar puncture and cerebrospinal fluid (CSF) analysis revealed pleocytosis (360/ mm; 50% neutrophils), low glucose, and high total protein levels. Immunophenotypic analysis detected no lymphoma cells in the CSF. The patient had grade 3 neutropenia and thrombocytopenia and grade 4 acute kidney injury. The serum C-reactive protein levels were markedly high. He tested negative for HIV. He was started on vancomycin, ceftriaxone, and ampicillin, but he soon developed septic shock and disseminated intravascular coagulation. Both blood and CSF cultures were positive for a methicillin-susceptible S. aureus (MSSA). Evaluation with the CT scans and a heart ultrasound did not reveal any other loci of infection. The patient was intubated and transferred to the intensive care unit where he died 2 days later. In large series, S. aureus has been identified as the cause of community-acquired meningitis in 1–6% of the cases [3–5]. In a series of 12,480 SAB cases, 81 cases (0.6%) of nonsurgical, community-acquired, bacteremic S. aureusmeningitis were identified; 61% of them had an unknown primary focus. Patients with neutropenia were excluded from the study [2]. Several molecular mediators for the pathogenesis of MCL have been identified. Bruton’s tyrosine kinase (BTK) is essential for B cell receptor (BCR) signaling. Aberrant BCR signaling is involved in the pathogenesis of MCL, while loss-offunction mutations of BTK result in X-linked agammaglobulinemia (XLA) [6], a non-lethal inherited immune deficiency, characterized by recurrent viral and bacterial infections from encapsulated bacteria and S. aureus [7]. Pyogenic central nervous system infections have also been reported [8]. The BTK inhibitor ibrutinib blocks BCR signaling and has been approved for the treatment of MCL. About one fourth of the patients treated with ibrutinib experience a serious infection and one case of non-fatal SAB was reported at the approval study [9], but no cases of meningitis have been reported. Ibrutinib use may mimic XLA, potentially placing patients in danger of severe bacterial infections. This case underscores the need for close monitoring of patients treated with BTK * Panagiotis T. Diamantopoulos pandiamantopoulos@gmail.com