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The concept of "accelerated" chronic lymphocytic leukemia is frequently used by both pathologists and clinicians. However, neither histological criteria to define this form of chronic lymphocytic leukemia nor its clinical correlates and prognostic impact have been formally defined in large series of patients.

The nucleoside analogue fludarabine is used in the treatment of chronic lymphocytic leukemia. It triggers p53-mediated apoptosis, although the mutational status of p53 does not fully account for heterogeneity in responsiveness to treatment. The aim of this study was to identify new genes implicated in fludarabine action as well as to determine the role of equilibrative nucleoside transporters (ENT) in the transcriptomic response triggered by this drug in chronic lymphocytic leukemia cells bearing wild type p53.

Mature T-cell malignancies of extracutaneous origin are rare disorders. T-cell prolymphocytic leukaemia (T-PLL) is the most common form of all mature T-cell leukaemias in adults. Secondary skill involvement by T-PLL has been reported in 25% of patients. A case of T-PLL which presented with cutaneous infiltration mimicking a cellulitis-like lesion resistant to antibiotic therapy is described. The diagnosis of T-PLL was subsequently fully supported by the clinical, laboratory and cytological findings, as well as by the immunophenotypic study of the skin biopsy. The present case stresses the importance of accurate evaluation of skin lesions in the diagnosis of some haematological conditions and gives additional information about T-PLL such as a previously non-reported cytogenetic abnormality [t(6;6)] and lack of cutaneous lymphocytic-associated antigen expression.

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinicobiological features. This translocation leads to fusion of MYST3 (MOZ) and CREBBP (CBP) genes, probably resulting in a disturbed transcriptional program of a myelomonocytic precursor. Nonetheless, its gene expression profile is unknown. We have analyzed the gene expression profile of 23 AML patients, including three with molecularly confirmed MYST3-CREBBP fusion gene, using oligonnucleotide U133A arrays (Affymetrix). MYST3-CREBBP cases clustered together and clearly differentiated from samples with PML-RAR alpha, RUNX1-RUNX1T1, and CBF beta-MYH11 rearrangements. The relative expression of 46 genes, selected according to their differential expression in the high-density array study, was analyzed by low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP AML cases. Thus, genes such as prolactin (PRL) and protooncogene RET were confirmed to be specifically overexpressed in MYST3-CREBBP samples whereas genes such as CCND2, STAM, and STAM were differentially underexpressed in this AML category. Interestingly, MYST3-CREBBP AML exhibited a characteristic pattern of HOX expression, with up-regulation of HOXA9, HOXA10, and cofactor MEISI and marked down-regulation of other homeobox genes. This lrofile, with overexpression of FLT3, HOXA9, MEIS1, AKR7A2,. CHD3, and APBA2, partially resembles that of AML with MLL rearrangement. In summary, this study shows the distinctive gene expression profile of MYST3-CREBBP AIM, with overexpression of RET and PRL and a specific pattern of HOX gene expression.

Purpose: The ZAP-70 gene is normally expressed in T and natural killer cells, where it is required for the T-cell receptor (TCR) signaling. More recently, it has been described that ZAP-70 contributes to the B-cell development at early stages of B-cell differentiation in mice. The purpose was to investigate the presence of ZAP-70 in normal pro/pre B cells and mature B cells and in tumoral cells from B-acute lymphoblastic leukemias (B-ALL). Experimental Design: ZAP-70 expression was ascertained by flow cytometry, immunofluorescence, Western blot, and quantitative reverse transcription-PCR. Analysis of ZAP-70 and other signaling proteins of the pre-TCR/TCR was done by Western blot. Results: ZAP-70 was expressed in pro/pre B cells but not in normal mature B cells derived from bone marrow, peripheral blood, or tonsil. Among tumoral cells, ZAP-70 was expressed in 56% of B-ALLs with pro/pre B-cell phenotype and in 4 of 6 Burkitt/ALL lymphomas. In B-ALL cells, expression of CD38 protein correlated with ZAP-70 expression (P = 0.05). Mutational analysis of the ZAP-70 gene revealed the absence of mutations in cases lacking ZAP-70 expression. Moreover, other elements of the pre-TCR/TCR signaling pathway, like LAT and Lck, were also found in B-ALL cells. Conclusions: Among normal B-cell subsets, ZAP-70 was found expressed in normal pro/pre B cells but not in a significant proportion of normal B cells with mature phenotype. Moreover, the presence of ZAP-70 in B-ALLs probably reflects their cellular origin. The lack of ZAP-70 expression in normal mature B cells suggests that its expression in mature-derived neoplasms with different cellular origin, such as Burkitt's lymphoma and chronic lymphocytic leukemia, might be due to an aberrant phenomenon.

The t(8;16)(p11;p13) fuses the MOZ (MYST3) gene at 8p11 with CBP (CREBBP) at 16p13 and is associated with an infrequent but well-defined type of acute myeloid leukemia (AML) that has unique morphocytochemical findings (monocytoid blast morphology with erythrophagocytosis and simultaneously positive for myeloperoxiclase and nonspecific esterases). RT-PCR amplification of MOZICBP (MYST3/CREBBP) chimera has proved difficult, with four different transcripts found in four reported cases. We studied 7 AML-t(8; 16) patients, 5 with cytogenetically demonstrated t(8; 16) and 2 with similar morphocytochemical and immunophenotypical characteristics. Clinically, 3 cases presented as therapy-related leukemia. Extramedullar involvement was observed at presentation in 2. patients and coagulopathy in 4. The clinicobiological findings confirmed the distinctiveness of this entity. Of note is the erythrophagocytosis in 5 of 7 cases and the immunological negativity for CD34 and CD 117 and positivity for CD56. Using a new RT-PCR strategy, we were able to amplify a specific band of 212 bp in six cases in which sequence analysis confirmed the presence of the previously described MOZICBP fusion transcript type 1. This is the largest molecularly studied AML-t(8; 16) series, which demonstrates that MOZICBP breakpoints are usually clustered in intron 16 of MOZ and intron 2 of CBP. The newly designed single-round PCR provides a simple tool for the molecular confirmation of MOZICBP rearrangement. (C) 2004 Wiley-Liss, Inc.

Background Acute myeloid leukemia (AML) after solid organ transplantation is rare, with only six AML cases after liver transplantation (LT) being reported. Methods. Characteristics of three AML cases observed among 799 recipients of LT in the authors' institution and estimation of the standardized incidence ratio (SIR) are presented. Results. Three AML cases were diagnosed (French-American-British classification subtypes M0, M3, and M1) at 38 days, 2 years, and 3.5 years after LT, respectively. The immunosuppressive regimen consisted of cyclosporine A and prednisone. The recipient's origin of blasts could be demonstrated in two cases. All patients achieved complete remission after standard treatment. Nonetheless, disease relapsed in two patients at 2 and 6 months, whereas the patient with acute promyelocytic leukemia remains disease-free 4 years after diagnosis. As compared with the general population, the observed incidence of AML in the authors' series of LT results in a significantly higher SIR of 11.41 (P=0.0023). Conclusions. The higher SIR found in the authors' series suggests an increased risk of AML in patients undergoing LT.

In a 56-year-old male patient, receiving chemotherapy after radical surgery for bladder carcinoma, an unusual type of cytoplasmic inclusion was discovered in about 30% of peripheral blood lymphocytes. This was a single, large (about 2 microns in diameter), round or ovoid body, darker than the nucleus and reddish-violet in May-Grünwald-Giemsa stain. The examination with transmission electron microscope demonstrated that such inclusions were made up of giant parallel tube arrays (PTAs). The absolute lymphocyte count was normal, but there was an expansion of CD3+, CD4-, CD8+, CD11b, TCR alpha beta lymphocytes. The lymphocytes bearing the inclusion were CD3+ and CD8+. DNA studies suggested an expansion of T-cell population with clonal rearrangement of TCR beta and TCR gamma. This case can be classified as an asymptomatic disorder of large granular lymphocytes, with unusual morphology. Giant PTAs should be taken into account in the differential diagnosis of lymphocyte cytoplasmic inclusions.

The Sysmex NE-8000 blood autoanalyser determines the values of red cells and platelets by impedance method and the differential leucocyte count (DLC) by means of radiofrequency plus two independent channels for eosinophils and basophils. The system is provided with a sampler capable of holding 100 closed tubes and its working velocity is about 120 samples per hour. The results of its evaluation are presented in this report. The parameters systematically provided by this cell counter include blood cell counts (plus haemoglobin rate, haematocrit and red cell indices), DLC platelet indices and volumetric distribution curves of red cells and platelets. The machine is provided with alarms on each of the above parameters for any suspicion of pathology. The accuracy analysis was performed with regard to the Technicon H*1 system and the conventional methods recommended by the ICSH. Precision, carry-over, linearity and effective velocity were evaluated in accordance to ICSH standards, and when assessing the DLC the number of visual revisions and the percentage of false positives and negatives were taken into account, and hence the sensitivity, specificity and efficiency of the machine. The accuracy of the parameters analysed was acceptable, except for MCHC and monocyte and eosinophil counts. A fair precision was found except for the monocyte count, along with excellent linearity except for high white-cell count. Less than 1.5% carry-over was observed, except for the leucocyte count. The number of necessary revisions of the DLC was somewhat higher than expected, the false negatives being below 11%. Sensitivity, specificity and efficiency were over 75%, except for hospital patients.(ABSTRACT TRUNCATED AT 250 WORDS)