Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies

Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 genemember of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 2012

Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2

Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized

Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

n/

Stress field of a near-surface basal screw dislocation in elastically anisotropic hexagonal crystals

In this study, we derive and analyze the analytical expressions for stress components of the dislocation elastic field induced by a near-surface basal screw dislocation in a semi-infinite elastically anisotropic material with hexagonal crystal lattice. The variation of above stress components depending on “free surface–dislocation” distance (i.e., free surface effect) is studied by means of plotting the stress distribution maps for elastically anisotropic crystals of GaN and TiB2 that exhibit different degrees of elastic anisotropy. The dependence both of the image force on a screw dislocation and the force of interaction between two neighboring basal screw dislocations on the “free surface–dislocation” distance is analyzed as well. The influence of elastic anisotropy on the latter force is numerically analyzed for GaN and TiB2 and also for crystals of such highly elastically-anisotropic materials as Ti, Zn, Cd, and graphite. The comparatively stronger effect of the elastic anisotropy on dislocation-induced stress distribution quantified for TiB2 is attributed to the higher degree of elastic anisotropy of this compound in comparison to that of the GaN. For GaN and TiB2, the dislocation stress distribution maps are highly influenced by the free surface effect at “free surface–dislocation” distances roughly smaller than ≈15 and ≈50 nm, respectively. It is found that, for above indicated materials, the relative decrease of the force of interaction between near-surface screw dislocations due to free surface effect is in the order Ti > GaN > TiB2 > Zn > Cd > Graphite that results from increase of the specific shear anisotropy parameter in the reverse order Ti < GaN < TiB2 < Zn < Cd < Graphite. The results obtained in this study are also applicable to the case when a screw dislocation is situated in the “thin film–substrate” system at a (0001) basal interface between the film and substrate provided that the elastic constants of the film and substrate are the same or sufficiently close to each other

A new synthesis of enantiomerically pure syn-(S)-β-hydroxy-α-amino acids via asymmetric aldol reactions of aldehydes with a homochiral Ni(II)-glycine/(S)-BPB Schiff base complex

syn-(S)-β-Hydroxy-α-amino acids were synthesised stereoselectively via elaboration of the asymmetric aldol reactions of aldehydes with a chiral Ni(II)-(S)-BPB/glycine Schiff base complex in the presence of equimolar NaH in THF. The stereoselectivity of the reaction was studied as a function of time, the reaction conditions, the nature of the carbonyl compounds and the base used. The synthetic potential of this asymmetric method was demonstrated in the preparation of syn-(S)-β-hydroxyleucine on a multi-gram scale.

Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of chromatin marks

Item does not contain fulltex

Nucleophilic addition to an achiral dehydroalanine Schiff base Ni(II) complex as a route to amino acids. A case of stereodetermining asymmetric protonation in the presence of TADDOL

We describe herein the elaboration of a new type of a substrate based on the Ni(II) complex of a Schiff base of dehydroalanine, 1, and Michael addition of nucleophiles to it, leading to the synthesis of racemic α-amino acids. We have also developed a catalytic method for the asymmetric 1,4 conjugate addition of achiral CH-acids to 1 promoted by TADDOLs with enantioselective catalytic protonation of the intermediate enolate in the stereodetermining stage of the reaction. A sizable 80% ee of the product was observed.

Thin-film solar cells on perlite glass-ceramic substrates

For the first time, thin-film CIGS solar cells have been fabricated by co-evaporation on specially developed non-conducting perlite (an aluminum potassium sodium silicate natural mineral of volcanic origin) glass-ceramic substrates to develop a fully integrated photovoltaic and building element. Such glass-ceramic material can meet the physical requirements to solar cells substrates as well as the cost goals. The preliminary data presented show that CIGS solar cells deposited on ceramic substrates can exhibit efficiency higher than 10%