Although the zeta-associated protein of 70 kDa (ZAP-70) is overexpressed in patients with chronic lymphocytic leukemia (CLL) displaying unmutated IGVH genes and poor prognosis, a previous microarray study from our group identified overexpression of LPL and ADAM29 genes among unmutated and mutated CLL, respectively. To assess the prognostic value of these genes, we quantified their expression by real-time quantitative polymerase chain reaction (
Key Points Some 10.1% of adults with non–Langerhans cell histiocytosis have a concomitant myeloid neoplasm with each often harboring distinct mutations. The presence of distinct kinase mutations in histiocytosis and myeloid neoplasms resulted in discordant responses to targeted therapy.
on behalf of the ANRS HC-13 Lympho-C Study Group Hepatitis C virus (HCV) infection increases the risk of B-cell non-Hodgkin lymphomas (B-NHL). Antiviral treatment (AT) can induce hematological responses in patients with marginal zone lymphomas (MZL). The ANRS HC-13 Lympho-C study aimed at a better understanding of the impact of AT on HCV associated B-NHL. This multicentric study enrolled 116 HCV-positive patients with B-NHL between 2006 and 2012. Cytological and histological samples were collected for centralized review. At lymphoma diagnosis, median age was 61 years and gender ratio M/F was 1. Cytohistological distribution was marginal zone lymphoma (MZL) n 5 45 (39%), diffuse large B-cell lymphoma (DLBCL) n 5 45 (39%), and other types n 5 26 (22%). MZL patients had more frequent detection of rheumatoid factor (68% vs. 35%; P 5 0.001) and more frequently mixed cryoglobulinemia (74% vs. 44%; P 5 0.021) than patients with DLBCL. Among patients receiving AT, a sustained virologic response was achieved in 23 of 38 (61%) patients with MZL and in 9 of 17 (53%) with DLBCL (P 5 0.42). Three-year overall survival (OS) and progression-free survival were 78% 95%CI and 64% , respectively, without difference between cytohistological groups. Outcome analysis showed a favorable association between OS and AT in all patients (P 5 0.05) and in the subgroup of MZL patients only (P 5 0.04). Our data support that AT improves the outcomes of HCV-associated NHLs. The impact of new AT regimen with protease inhibitor needs to be investigated in this setting. [clinicalTrials.gov Identification number NCT01545544]Am.
BackgroundPlasmodium falciparum immature gametocytes accumulate in the bone marrow, but their exact location in this tissue remains unclear.MethodsThe stage and deposition pattern of gametocytes was analysed on histological sections of a bone marrow sample collected in a patient with subacute P. falciparum malaria.ResultsA majority (89%) of immature stages II to IV gametocytes and a minority (29%) of mature stage V gametocytes were observed in extravascular spaces.Discussion and conclusionThese observations represent a valuable step towards understanding sequestration patterns of P. falciparum gametocytes and may ultimately lead to novel transmission-blocking interventions.
Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a IntroductionActivating mutations of genes encoding protein tyrosine kinases are known to participate in malignant leukemogenesis in humans. Along with the well-known involvement of ABL1, KIT, and FLT3 genes, attention has been drawn to the JAK family members. These genes encode cytoplasmic protein tyrosine kinases associated with the intracellular region of cytokine receptors and essential to their activity. Chromosomal translocations were the first-described genetic lesions affecting JAK2, in both acute leukemia or myeloproliferative disease (MPD). They lead to the expression of fusion proteins containing the carboxy-terminus part of JAK2 and an amino-terminal portion of TEL, 1,2 BCR, 3 or PCM1 4-6 that generally possess constitutive kinase activity.The most frequent-activating mutation affecting the JAK2 gene in human diseases is a valine-to-phenylalanine substitution at amino acid 617 (V617F) present in a subtype of MPD (reviewed in James et al 7 ). Interestingly, the wild-type JAK2 copy is frequently lost in patients with polycythemia vera (PV), resulting from duplication of the mutated copy through mitotic recombination. The V617F mutation is located within the JAK homology 2 (JH2) pseudokinase, or inhibitory domain of the protein. It leads to constitutive JAK2 activation and confers growth factor hyperresponsiveness or independency to the Ba/F3 cell line. When assayed in bone marrow transplantation experiments, JAK2V617F recapitulates most of the clinical features of human PV. [8][9][10] Contrasting with its high frequency in MPD, JAK2V617F is a rare event in acute myeloblastic leukemia (AML) that is essentially limited to cases of AML that develop following MPD. [11][12][13][14] We hypothesized that somatic JAK2 mutations could be associated with increased expression of the mutated gene. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we evaluated the expression of JAK2 in a series of 90 acute leukemias of myeloid or B-cell origin. We identified an activating JAK2 mutation in a patient with DS with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) associated with high expression of the mutated JAK2 allele. Materials and methods Quantitative RT-PCRTotal RNA was extracted using RNAble reagent (Eurobio, Courtaboeuf, France). Reverse transcription was carried out with 4 g RNA using random hexamers and Moloney Murine Leukemia Virus Reverse Transcriptase (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. cDNAs were amplified using TaqMan Universal PCR Master Mix (Applied BioSystem, Foster City, CA) and 10 pmoles of primers and probes; reactions wer...
Key Points B-PLL is tightly linked to MYC aberrations (translocation or gain) and 17p (TP53) deletion. Cases of B-PLL with MYC aberration and 17p (TP53) deletion have the worst prognosis.
Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.
Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including IGHV mutational status, cytogenetic abnormalities and, more recently, LPL/ADAM29 expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of IGHV gene status, LPL and ADAM29 gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16-74) months. Sequencing of IGHV showed mutated (M) VH genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of LPL and ADAM29 expression in 35 of 41 cases showed overexpression of ADAM29 in 17 cases (14 M and three UM) and LPL in 18 cases (all UM). Patients expressing UM IGHV and LPL had shorter DFS and OS when compared to patients expressing M IGHV and/or ADAM29. Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD(+). Our results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.
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