Classification of myelodysplastic syndromes 2015

The Myelodysplastic syndromes are a heterogeneous group of hematological malignancies difficult to diagnose and classify, for which novel treatments are beginning to emerge. Recent advance in diagnosis classification, prognosis scoring and genetics discovery are presented in this update

t(5;11)(q33;q13) NUMA1/PDGFRB a novel fusion

A novel NUMA1/PDGFRB fusion identified in B-cell precursor acute lymphoblastic leukemia is described

Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine

•Cytogenetic findings are strong predictor for survial in AZA-treated MDS patients.•Isolated del(7q) had similar survival as patients with normal karyotype.•Cytogenetic abnormalities don’t predict response to AZA.•Achieving cytogenetic response has a limited effect on outcomes in AZA-treated patients. Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10−4) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies

Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations and clinical impact

Recent evidence suggests that complex karyotype (CK) defined by the presence of 653 chromosomal aberrations (structural and/or numerical) identified by chromosome banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges towards routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with 655 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcome, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and or TP53 mutations, TP53abs) and the expression of somatically hypermutated (M-CLL) or unmutated (U-CLL) immunoglobulin heavy variable genes (IGHV). Thus, they contrasted CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs and IGHV gene somatic hypermutation status, we propose a novel hierarchical model where patients with high-CK exhibit the worst prognosis, while M-CLL lacking CK or TP53abs as well as CK with +12,+19 show the longest overall survival. In conclusion, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with 655 chromosomal aberrations emerges as prognostically adverse, independently of other biomarkers. Prospective clinical validation is warranted before finally incorporating high-CK in risk stratification of CLL

Analyse des altérations structurales du génome dans la Leucémie Lymphoïde Chronique (apport de l hybridation génomique comparative sur puces à ADN (CGH array))

La leucémie Lymphoïde Chronique (LLC) est la plus fréquente des hémopathies occidentales. Les anomalies génétiques détectées par la technique d hybridation in situ par fluorescence (FISH) ont une valeur pronostique bien établie. Dans ce travail, j ai étudié les anomalies génétiques de la LLC à l aide de plusieurs techniques. La FISH a été la méthode la plus sensible pour détecter la présence d une délétion dans la région 13q14, ciblée sur le marqueur D13S319, dans 54% des cas d une cohorte de 314 patients. La représentativité du clone variait de 7 à 90% ; le plus souvent monoallélique, la délétion portait sur les 2 allèles dans 9% des cas et des délétions mono- et bi-alléliques coexistaient dans 15% des cas. Nous avons réalisé une étude en Hybridation Génomique Comparative sur micro-puces recouvertes d oligonucléotides (CGH-a) qui permet de quantifier les copies d un gène sur l ADN de patients par rapport à un témoin. Nous avons ainsi observé une grande variation de la taille de la délétion allant d une région minimale, restreinte à une zone appelée BCMS comprenant les MicroARN 15 et 16, à une grande région de 60 M bases couvrant une zone allant du gène du Rétinoblastome à celui de la protocadherine. La CGH nous a également permis dans 3 cas, de mettre en évidence une délétion sur le chromosome 14, impliquant notamment le gène codant les immunoglobulines. Nous avons identifié un gène de fusion impliquant un nouveau partenaire : ZFP36L1 membre de la famille des tristétraprolines facteurs régulateurs de la transcription. Le rôle fonctionnel de ce nouveau transcrit dans la leucémogenèse est en cours d étude.B-cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in western countries. Genomic abnormalities detected by Fluorescence in situ hybridization (FISH) are emerging prognostic indicators important in CLL. These ones are observed in about 80% of CLL patients and have been associated to defined subgroups with different clinical outcomes. In this project, different techniques have been performed aiming at the identification of new genetic abnormalities in CLL. FISH was the most sensitive one, identifying deletion del13q14 in 54% of 314 patients with a restriction to the D13S319 marker. We showed that the del13q deletion was heterogeneous and the clonality of the deletion was highly variable, ranging from 7 to 90 %, monoallelic in most cases but biallelic in 9.5% and concomitantly mono and bi-allelic in 15% of the cases.We also used Comparative Genomic Hybridization performed on DNA array (CGH-a) that measured differences in DNA copy number between patients and reference genomes. We observed variable sizes of deletion ranging from a Minimal deleted region (BCMS) including microRNAs 15 /16 to a very large region of 60 Mb, including RB1 or protocadherin in the opposite sides. CGH-array allowed to detect a deletion del14q in 3 cases, with a fusion between Immunoglobulin gene and a new partner that we identified as ZFP36L1 a member of the tris tetrapolin family of proteins involved in mRNA decay. The functional role of this new fusion gene in leukemogenesis is currently under study.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Néo-matériau hybride de séquestration de principe actif à usage alimentaire et son procédé de fabrication

The present invention relates to a novel hybrid material for sequestering active principle in a concentrated fluid emulsion comprising: - a hydrophobic core comprising at least one active principle provided with at least one aromatic ring, - a layer of anionic surfactant of lipophilic carboxylic acid salt type, - a monodisperse lipid phase dispersed in a continuous aqueous phase, said lipid phase comprising at least one lipid amphoteric surfactant bearing at least two fatty acid chains, a glyceryl group and an ionized head, - a surface layer of amphiphilic nonionic surfactant bearing a hydrophobic element functionalized by one, two or three free hydroxyl groups and a mixed hydrophilic element constituted by a glyceryl group and a polyethylene glycol chain. A process that makes it possible to obtain such a material, the use of this material for producing food products and also the food products comprising such a material are also claimed.La présente invention concerne un néo-matériau hybride de séquestration de principe actif dans une émulsion fluide concentrée comprenant : -un coeur hydrophobe comprenant au moins un principe actif doté d'au moins un cycle aromatique, -une couche de tensioactif anionique de type sels d'acides carboxyliques lipophiles, -une phase lipidique monodisperse dispersée dans une phase aqueuse continue, ladite phase lipidique comprenant au moins un tensioactif amphotère lipidique portant au moins deux chaînes d'acides gras, un groupement glycéryl et une tête ionisée, -une couche superficielle de tensioactif non-ionique, amphiphile portant un élément hydrophobe fonctionnalisé par un, deux ou trois groupes hydroxyles libres et un élément hydrophile mixte constitué par un groupement glycéryl et une chaîne polyéthylène glycol. Un procédé permettant d'obtenir un tel matériau, l'utilisation de ce matériau pour la réalisation de produits alimentaires ainsi que les produits alimentaires comprenant un tel matériau sont également revendiqués

Néo-matériau hybride de séquestration de principe actif à usage alimentaire et son procédé de fabrication

La présente invention concerne un néo-matériau hybride de séquestration de principe actif dans une émulsion fluide concentrée comprenant : -un coeur hydrophobe comprenant au moins un principe actif doté d'au moins un cycle aromatique, -une couche de tensioactif anionique de type sels d'acides carboxyliques lipophiles, -une phase lipidique monodisperse dispersée dans une phase aqueuse continue, ladite phase lipidique comprenant au moins un tensioactif amphotère lipidique portant au moins deux chaînes d'acides gras, un groupement glycéryl et une tête ionisée, -une couche superficielle de tensioactif non-ionique, amphiphile portant un élément hydrophobe fonctionnalisé par un, deux ou trois groupes hydroxyles libres et un élément hydrophile mixte constitué par un groupement glycéryl et une chaîne polyéthylène glycol. Un procédé permettant d'obtenir un tel matériau, l'utilisation de ce matériau pour la réalisation de produits alimentaires ainsi que les produits alimentaires comprenant un tel matériau sont également revendiqués.The present invention relates to a novel hybrid material for sequestering active principle in a concentrated fluid emulsion comprising: - a hydrophobic core comprising at least one active principle provided with at least one aromatic ring, - a layer of anionic surfactant of lipophilic carboxylic acid salt type, - a monodisperse lipid phase dispersed in a continuous aqueous phase, said lipid phase comprising at least one lipid amphoteric surfactant bearing at least two fatty acid chains, a glyceryl group and an ionized head, - a surface layer of amphiphilic nonionic surfactant bearing a hydrophobic element functionalized by one, two or three free hydroxyl groups and a mixed hydrophilic element constituted by a glyceryl group and a polyethylene glycol chain. A process that makes it possible to obtain such a material, the use of this material for producing food products and also the food products comprising such a material are also claimed