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In developing methods for the preliminary chemical modification of nonpolar sulfur-containing compounds for their subsequent effective study by "soft" ionization [electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI)] mass spectrometry, a rather unexpected possibility of implementing S-alkylation of analytes with polydialkylsiloxanes in the presence of trifluoromethanesulfonic acid (CF3SO3H) as a superacid co-alkylating agent has been found. The ESI and MALDI mass spectra show that the corresponding S-alkylsulfonium salts are formed in both cases. However, in using polydimethylsiloxane, it is not possible to choose reaction conditions that would provide reproducible product yields. At the same time, in the case of polydiethylsiloxane, the reaction proceeds with an almost quantitative yield, regardless of the structure of the initial thiabicycloalkane. Subsequent studies of derivatization products are best performed using MALDI mass spectrometry, which allows the detection of target signals with high signal-to-noise ratios. In the case of ESI, the spectra are sometimes noticeably noisy with extraneous peaks, obviously due to hydrolysis and condensation products. A rational mechanism of the described chemical transformation is proposed, including indispensable activation by the trifluoromethanesulfonic acid accompanied by the rupture of the Si–C bond and the release of an alkyl cation modifying the sulfide. The effects of the structure and regio-isomerism on the collision-activated dissociation mass spectra of S-ethylated bicyclic sulfonic cations are considered. [ABSTRACT FROM AUTHOR]

Switches from the lymphoid to myeloid lineage during B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment are considered rare and thus far have been detected in MLL-rearranged leukemia. Here, we describe a novel BCP-ALL subset, switching BCP-ALL or swALL, which demonstrated monocytosis early during treatment. Despite their monocytic phenotype, 'monocytoids' share immunoreceptor gene rearrangements with leukemic B lymphoblasts. All swALLs demonstrated BCP-ALL with CD2 positivity and no MLL alterations, and the proportion of swALLs cases among BCP-ALLs was unexpectedly high (4%). The upregulation of CEBPα and demethylation of the CEBPA gene were significant in blasts at diagnosis, prior to the time when most of the switching occurs. Intermediate stages between CD14negCD19posCD34pos B lymphoblasts and CD14posCD19negCD34neg 'monocytoids' were detected, and changes in the expression of PAX5, PU1, M-CSFR, GM-CSFR and other genes accompanied the switch. Alterations in the Ikaros and ERG genes were more frequent in swALL patients; however, both were altered in only a minority of swALLs. Moreover, switching could be recapitulated in vitro and in mouse xenografts. Although children with swALL respond slowly to initial therapy, risk-based ALL therapy appears the treatment of choice for swALL. SwALL shows that transdifferentiating into monocytic lineage is specifically associated with CEBPα changes and CD2 expression. [ABSTRACT FROM AUTHOR]

The expression of CD27 and CD44 correlate with the genotype of B-precursor acute lymphoblastic leukemia (ALL). Based on the expression of these antigens, we identified counterparts of TEL/ AML1pos and TEL/ AML1neg leukemic cells in nonmalignant bone marrow. Although CD27 is known as a marker of mature memory B cells, we recently showed that CD27 is also expressed by malignant and nonmalignant B precursors. Here, we show that CD27 and CD44 delineate stages of B-precursor development. Well-established differentiation markers showed that the developmental sequence starts from undetermined progenitors, expressing CD44. Upon B-lineage commitment, cells gain CD27 and lose CD44. The CD27posCD44neg (CD27 single positive, 27SP) cells are the earliest stage within CD10posCD19pos B precursors and express RAG-1 and TDT. These cells correspond to TEL/ AML1pos ALL (1/4 pediatric B-precursor ALL). The development follows to CD27/CD44 double-positive (27/44DP) stage, 44SP stage and CD27/CD44 double-negative (27/44DN) stage. Before exit to periphery, CD44 is reexpressed. The 27/44DP cells are mostly large and profoundly suppress RAG-1. Despite their presumably high proliferation potential, 27/44DP cells rarely dominate in leukemia. At 44SP stage, which corresponds to TEL/ AML1neg leukemias, RAG-1 is reexpressed and Ig light chain gene starts to be rearranged. [ABSTRACT FROM AUTHOR]

L-Asparaginase is a standard component in chemotherapy of childhood acute lymphoblastic leukaemia (ALL). Leukaemic cells carrying TEL/AML1 fusion gene are more sensitive to treatment with L-asparaginase compared to other subtypes of ALL. We demonstrate in vitro the prolonged growth suppression of TEL/AML1[+] cells compared to TEL/AML1[-] leukaemic cells after L-asparaginase treatment simulating treatment protocol. Cell cycle analysis revealed TEL/AML1[+] cells to accumulate in G1/G0 phase (81-98%) compared to TEL/AML1[-] cells (47-60%). Quantitative analysis of asparagine synthetase (AsnS) expression showed the ability of TEL/AML1[+] cells to increase AsnS mRNA levels after L-asparaginase treatment to the same extent as TEL/AML1[-] leukaemic and nonleukaemic lymphoid cells. We hypothesise that TEL/AML1[+] cells are unable to progress into the S phase of cell cycle under nutrition stress caused by L-asparaginase, despite the ability of AsnS upregulation. Significantly higher expression of AsnS was found in untreated leukaemic cells from children with TEL/AML1[+] ALL (n=20) in comparison with the group of age-matched children with ALL bearing no known fusion gene (n=25; P=0.0043). Interestingly, none of the TEL/AML1[+] patients with high AsnS level relapsed, whereas 10/15 patients with AsnS below median relapsed (P=0.00028). Therefore, high AsnS levels in TEL/AML1[+] patients correlate with better prognosis, possibly reflecting the stretched metabolic demand of the lymphoblast.Leukemia (2004) 18, 434-441. doi:10.1038/sj.leu.2403259 Published online 15 January 2004 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about upregulation of asparagine synthetase and cell cycle arrest in t (12;21)-positive acute leukemia.

Presents a letter to the editor about statistical difference in asparagine synthetase expression levels in TEL/AML1 paediatric acute leukemia patients with or without subsequent relapses.