The common beta chain subunit (βc), also known as CDw131, shared by the interleukin-3 (IL-3), granulocytic macrophage colony-stimulating factor (GM-CSF) and IL-5 receptors, is required for high-affinity ligand binding and signal transduction. The present study explored the expression of CDw131 in 105 de novo cases of acute myeloid leukaemia (AML). The levels of CDw131 expression were used to identify two AML subgroups characterized by low (75/105) and high (30/105) expression of this receptor chain. It was observed that (i) the level of CDw131 expression strictly correlated with the level of CD116 (GM-CSFα receptor chain) and CD123 (IL-3Rα chain); (ii) AMLs with high CDw131 expression were characterized by low CD34 expression and usually high CD11b, CD14 expression; (iii) AMLs with high CDw131 expression frequently co-expressed receptors for angiogenic growth factors (vascular endothelial growth factor R2, Tie-2); (iv) AMLs with high CDw131 expression were more cycling than those with low CDw131 expression; (v) AMLs with high CDw131 frequently displayed Feline Murine Sarcoma (FMS-related) tyrosine kinase 3 (FLT3) internal tandem duplication and constitutively activated Signal Transducer and Activator of Transcription-5 (STAT5). In conclusion, the analysis of the level of CDw131 expression enabled the identification of a subset of AMLs characterized by a high cycling status, the expression of myelo-monocytic markers, mutated FLT3 and the co-expression of receptors for angiogenic growth factors. These findings are of value for the development of new therapeutic strategies for the treatment of these AMLs. © 2008 The Authors

SummaryThe present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor-related-apoptosis-inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French-American-British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib-sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase-8 and caspase-3 and decreased cellular FLICE [Fas-associated death domain (FADD)-like interleukin-1b-converting enzyme]-inhibitory protein (c-FLIP) levels in AML blasts; (ii) high c-FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an antileukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.

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ABSTRACT

Summary:chronic myeloid leukemia (CML) relapsed after allogeneic bone marrow transplantation (BMT). [1][2][3][4][5] Chimerism studies in patients who relapsed following an Recent observations of chimerism in patients relapsed following an allotransplant suggest the persistence of allotransplant suggest the persistence of immunotolerance thus offering a biologic rationale for the use of DLT. 6 Sevimmunotolerance, thus offering a biologic rationale for the use of donor lymphocyte transfusion (DLT). In this eral methods with different sensitivities are useful to evaluate the chimerism status in transplanted patients. These study, we have analyzed by PCR amplification of several VNTR regions, sequential bone marrow and peripheral include cytogenetics, Y body detection, protein polymorphism, and red cell phenotyping. 7-9 More recently, DNAblood DNA samples in four patients who received DLT for CML relapse after bone marrow transplantation.based methodology has provided more sensitive techniques. In particular, polymerase chain reaction (PCR) amplifiPrior to DLT, all patients showed mixed chimerism in peripheral blood cells while two had mixed chimerism cation of individual specific genetic loci, such as the variable tandem repeats (VNTR) and the short tandem repeats and two no chimerism in the BM. None of these four patients showed evidence of chimerism at the cyto-(STR), have increased the sensitivity of the analysis up to 1-0.1% and 0.1-0.01%, respectively. 10,11 Using these genetic level (all had 100% +ve metaphases). After DLT, a complete hematologic and molecular remission (ie disassays, a condition of mixed chimerism (MC) has been shown in 80% of CML patients receiving T cell-depleted appearance of the BCR/ABL fusion transcript) was obtained in the two patients who had bone marrow allografts. 11 With regard to CML patients treated with DLT for mixed chimerism prior to DLT. The two patients without evidence of marrow chimerism prior to DLT conrelapse after BMT, Mackinnon et al 12 have analyzed the chimerism status of T lymphocytes by PCR and shown that verted to a pattern of mixed chimerism after DLT, but both developed a severe bone marrow aplasia occurring a MC was present in almost every patient prior to DLT. While this observation encourages the use of adoptive at day 56 and 36, respectively. With regard to the sequential analysis of bone marrow chimerism after immunotherapy in these patients, it provides no prognostic information on the post-DLT clinical outcome. DLT we observed that: (1) the disappearance of BCR/ABL +ve cells paralleled the conversion to a patIn this study, we have analyzed by PCR amplification of several VNTR regions sequential bone marrow and periphtern of full donor chimerism; and (2) the time interval to achieve CR was inversely correlated with the percenteral blood DNA samples in four patients who received DLT for CML relapse after BMT. We show that bone marrow age of donor DNA in bone marrow. In conclusion, we have shown here that the assessment of bone marrow chimerism pre-DLT is pr...