The role of the K247R substitution in the ABL tyrosine kinase domain in sensitivity to imatinib

Imatinib mesylate has become the gold standard front-line treatment of chronic myelogenous leukemia through its ability to inhibit ABL tyrosine kinase. Resistance to this inhibition may occur. We investigated the role of the K247R polymorphism in persistent sensitivity.     

Chondroid syringoma

This is a retrospective monocentric stydy of all the cases diagnosed at our department over a period of 10 years. The study included seven male patients. All patients presented with a single painless skin lesion of about 1,5 cm on the face, lasting for 14 months on average. In all cases, treatment was surgical and the outcome satisfactory. Chondroid syringoma is a benign sweat gland tumor. This lesion is electively located in the craniofacial area, made of a subcutaneous painless tumor measuring from 0.5 to 3 cm. Diagnosis can always be confirmed by histology which shows tubuloalveolar and gland like structures with two or more cuboidal cell lines in a fibroadipoid or chondroid stroma that is positively stained for Alcian blue. Mixed tumors have a slow course; their progress to malignancy is rare but possible. The best treatment remains surgical allowing a histological diagnosis with a control of the lesion edges.     

Total absence of protein 4.2 and partial deficiency of band 3 in hereditary spherocytosis

Unlike previously reported cases with total protein 4.2 deficiency due to mutations in the EPB42 gene, we describe a total deficiency in protein 4.2 with normal EPB42 alleles. Hereditary spherocytosis (HS) was observed in a Japanese woman (unsplenectomized) and her daughter (splenectomized). The mother showed a partial deficiency in band 3 and a proportional reduction in protein 4.2. She was heterozygous for a novel allele of the EPB3 gene, allele Okinawa, which contains the two mutations that define the Memphis II polymorphism (K56E, AAG → GAG, and P854L, CCG → CTG) and, additionally, the mutation: G714R, GGG → AGG, located in a highly conserved position of transmembrane segment 9. The latter change was responsible for HS. In trans to allele Okinawa, the daughter displayed allele Fukuoka: G130R, GGA → AGA, an allele known to alter the binding of protein 4.2 to band 3. The daughter presented with a more pronounced decrease of band 3, and lacked protein 4.2, resulting in aggravated haemolytic features. Although the father was not available for study, heterozygosity for allele Fukuoka has been documented in another individual who showed no clinical or haematological signs, and a normal content of band 3. We suggest that band 3 Okinawa binds virtually all the protein 4.2 in red cell precursors, band 3 Fukuoka being unable to do so, and that the impossibility of band 3 Okinawa incorporation into the membrane leads to degradation of the band 3 Okinawa protein 4.2 complex. In contrast, band 3 Fukuoka, free of bound protein 4.2, could then incorporate normally into the bilayer. Thus, protein 4.2 would not appear in the daughter's red cell membrane.     

Ankyrin Napoli: a de novo deletional frameshift mutation in exon 16 of ankyrin gene (ANK1) associated with spherocytosis

We report a case of apparently recessive hereditary spherocytosis in an Italian child. The proband exhibited a reduction of overall ankyrin in the red cell membrane. The parents were free of any haematological manifestations. The VNDR associated with the ankyrin gene (ANK1) were consistent with the following diplotypes: AC₁₁/AC₁₄ (father), AC₁₄/AC₁₄ (mother) and AC₁₁/AC₁₄ (child). The cDNA of the patient disclosed the expression of the AC₁₁ allele only. As a consequence, we put forward the hypothesis of a de novo inactivation affecting the ankyrin allele of maternal origin (AC₁₄) and accounting for the disease. PCR amplification of exons, SSCP analysis and nucleotide sequencing disclosed a polymorphism: GAC → AAC; Asp → Asn in codon 328 of exon 10, and a one-nucleotide deletion : CTG → CG in codon 573 of the exon 16. This frameshift mutation placed in phase the TGA triplet that normally overlaps codons 636 and 637. Termination of translation near the middle of ankyrin mRNA coding sequence resulted, presumably, in its premature degradation. The present allele has been designated allele Napoli.     

Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation

We analyzed 27 CML patients treated with imatinib (IM) who developed a BCR-ABLT315I mutation. These patients had poor prognostic features: High or intermediate Sokal index (82%), and lack of CCyR under IM (59%). At T315I discovery, patients were in advanced phase (59%), with clonal evolution (84%). Median time since diagnosis was 39 months, and progression occurred 13 months after IM initiation, regardless of disease phase. Overall survival since IM initiation was 42.5 months for chronic, and 17.5 months for advanced phases, and all patients progressed. This mutation seems related to or (partially?) responsible for progression and poor survival.     

In Vitro Activities of Strychnos Alkaloids and Extracts against Plasmodium falciparum

The in vitro antimalarial activities of 46 alkaloids and extracts from Strychnos species were evaluated. Two types of quasidimeric alkaloids exhibit high and selective activities against Plasmodium. Strychnopentamine and isostrychnopentamine were active against chloroquine-sensitive and -resistant strains (50% inhibitory concentration [IC(50)] approximately 0.15 microM), while dihydrousambarensine exhibited a 30-fold higher activity against the chloroquine-resistant strain (IC(50) = 0.03 microM) than it did against the chloroquine-sensitive strain.