Chronic lymphocytic leukemia and prolymphocytic leukemia: a clinicopathological reappraisal

A series of 300 cases of chronic B-cell leukemia was studied in relation to clinical and laboratory features, and three groups were identified on the basis of the percentage of circulating prolymphocytes (%PROL): typical CLL less than or equal to 10% PROL, 174 cases; PLL greater than 55% PROL, 42 cases; and an intermediate group CLL/PL (11%-55% PROL), 84 cases. Some features of the CLL/PL group resemble those of PLL, such as a disproportionate splenomegaly in relation to the degree of lymphnode involvement. However, membrane markers suggested a closer affinity of CLL/PL with CLL [high percentage of M rosettes, expression of the P67 (T1) antigen, and low reactivity with the McAb FMC7], although high-density SmIg was found in one-third of CLL/PL, as well as in the majority of the PLL cases. Cells volume measurements demonstrated that the prolymphocytes of both PLL and CLL/PL are significantly larger than the homogeneous population of small lymphocytes of typical CLL. Followup studies of the PB picture in CLL and CLL/PL showed that the majority of patients maintain a relatively stable percentage of PROL, but a progressive prolymphocytoid transformation to a PLL-like disease may occur in some cases. On univariate analysis of survival, seven features of disease had a high prognostic values for the whole group of patients: %PROL, absolute number of PROL (ABS PROL), WBC, spleen size, M rosettes, SmIg intensity, and age. However, only ABS PROL (greater than 15 X 10(9)/l) and spleen size (greater than 8 cm) were shown to be independent prognostic features on a multivariate regression analysis. The median survival time of patients with PLL (3 years) was significantly shorter than the median of 8 years for patients with CLL. Within the heterogeneous CLL/PL group, patients with ABS PROL greater than 15 X 10(9)/l (two-thirds) had a median survival time as bad as for PLL patients, whereas the median has not been reached for those with ABS PROL less than 15 X 10(9)/l.     

Evidence for monoclonal proliferation in prolymphocytic leukemia of T-cell orgin. A cytogenetic and Quantitative immunoautoradiographic analysis.

B- and T-cell markers were studied in a patient with prolymphocytic leukemia, a rare variant of chronic lymphocytic leukemia. Thymus-derived features were identified on the membrane of the neoplastic lymphocytes using the following cellsurface markers: Heterologous T-cell antigen, sheep erythrocyte receptor, surface immunoglobulin, complement receptor, Fc receptor and mouse erythrocyte receptor. Cytogenetic studies of leukemic cells from unstimulated and mitogen-stimulated cultures revealed a consistent karyotype characterized by marker chromosomes and a decreased chromosome number, whereas chromosomal analysis of hair root cells yielded a normal karyotype. A uniform expression of T-cell antigens measured on single leukemic cells by quantitative microphotometric immunoautoradiography correlated with the cytogenetic findings which are compatible with a descent from one progenitor cell.     

Human T-cell leukemia virus type 1 (HTLV-1) latency

Comment on: Abou-Kandil A, et al. Cell Cycle 2011; 10:3337-45.     

Adult T-cell leukemia with an unusual phenotype, Leu-2a positive and Leu-3a negative

A case of adult T-cell leukemia (ATL) with an unusual phenotype is presented. Leukemia cells of this patient reacted with anti-Leu-2a monoclonal antibody, although most of ATL cases are reported to show the phenotype of helper/inducer T-cell. It is indicated that the surface phenotype of ATL is rather heterogeneous.     

(11; 14) translocation in three boys with acute lymphoblastic leukemia of T-cell immunophenotype

Three boys, 12, 15 and 5 years old are presented with acute lymphoblastic leukemia resp. Non-Hodgkin's lymphoma with leukemic transformation. Blast cells could be characterized as being of T-cell origin. Hand mirror variant was the predominant morphologic feature of the blast cells in two patients. Chromosome analysis of the leukemic blast cells revealed a pseudodiploid (modal chromosome number = 46) karyotype in two patients and a pseudotetraploid (modal chromosome number = 92) in one patient. A chromosome translocation (11; 14) with breakpoints at (p 13; q 13) (within the human T-cell receptor alpha chain locus!) was found in the leukemic cells of all three cases plus an additional t (7; 9) (q 22; p 13) in one patient.     

Immunoglobulin heavy chain and alpha T-cell receptor genes rearrange in T-cell leukemia associated with a t(14;14) (q11.2;q32) translocation

We report here a cytogenetic and molecular analysis of two cases of T-cell leukemia with t(14;14) (q11.2;q32). Through in situ hybridization and Southern blotting, using radioactively labeled immunoglobulin heavy chain (IGH) and alpha T-cell receptor (TCRA) gene probes, we found in both tumors that the loci of both IGH and TCRA were rearranged. Molecular analysis of the t(14;14) clearly demonstrated that in some tumors rearrangements of the IGH and TCRA genes are associated with interchromosomal exchanges that result in specific chromosome translocations that confer a proliferative advantage and predisposition to leukemic transformation. The implication of these rearrangements for normal and neoplastic T-cell development is discussed.     

Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans

The major receptors required for attachment and entry of the human T-cell leukemia virus type 1 (HTLV-1) remain to be identified. Here we demonstrate that a functional, soluble form of the HTLV-1 surface envelope glycoprotein, gp46, fused to an immunoglobulin Fc region (gp46-Fc) binds to heparan sulfate proteoglycans (HSPGs) on mammalian cells. Substantial binding of gp46-Fc to HeLa and Chinese hamster ovary (CHO) K1 cells that express HSPGs was detected, whereas binding to the sister CHO lines 2244, which expresses no HSPGs, and 2241, which expresses no glycosaminoglycans (GAGs), was much reduced. Enzymatic removal of HSPGs from HeLa and CHO K1 cells also reduced gp46-Fc binding. Dextran sulfate inhibited gp46-Fc binding to HSPG-expressing cells in a dose-dependent manner, whereas chondroitin sulfate was less effective. By contrast, dextran sulfate inhibited gp46-Fc binding to GAG-negative cells such as CHO 2244, CHO 2241, and Jurkat T cells weakly or not at all. Dextran sulfate inhibited HTLV-1 envelope glycoprotein (Env)-pseudotyped virus infection of permissive, HSPG-expressing target cells and blocked syncytium formation between HTLV-1 Env-expressing cells and HSPG-expressing permissive target cells. Finally, HSPG-expressing cells were more permissive for HTLV-1 Env-pseudotyped virus infection than HSPG-negative cells. Thus, similar to other pathogenic viruses, HTLV-1 may have evolved to use HSPGs as cellular attachment receptors to facilitate its propagation.     

T-helper phenotype chronic lymphocytic leukemia (Thp-CLL): characterization of an Italian case with particular biological findings

A patient with Chronic Lymphocytic Leukemia (CLL) characterized by an expansion of helper phenotype mature T lymphocytes is here described. The phenotype of these cells was OKT3+, OKT4+, Leu 9+, 5/9+, OKT8-, Tac- and functional studies showed a strong helper activity on B cell differentiation; an "in vivo" presence of an IgG-lambda paraproteinaemia has been demonstrated. Cytogenetic studies showed multiple clonal, numerical and structural rearrangements which included a tandem t(14;14) (q11;32) translocation. Hybridization showed HTLV I related specific bands indicating the presence of exogenous sequences related to prototype virus but derived from a different Retrovirus (HTLV 1c). The clinical course was aggressive and unsuccessful treatments with various polichemotherapeutic protocols, associated with multiple leukaphereses, were performed. The authors underline that despite the morphological, immunological, biological and virological heterogeneity, the common feature of T-helper CLL is the inexorable clinical course which needs a new therapeutic approach.     

Multicentric T-cell lymphoma associated with feline leukemia virus infection in a captive namibian cheetah (Acinonyx jubatus)

This case report describes a multicentric lymphoma in a 4 yr old female wildborn captive cheetah (Acinonyx jubatus) in Namibia after being housed in an enclosure adjacent to a feline leukemia virus (FeLV) infected cheetah that had previously been in contact with domestic cats. The year prior to the onset of clinical signs, the wild-born cheetah was FeLV antigen negative. The cheetah subsequently developed lymphoma, was found to be infected with FeLV, and then rapidly deteriorated and died. At necropsy, the liver, spleen, lymph nodes, and multiple other organs were extensively infiltrated with neoplastic T-lymphocytes. Feline leukemia virus DNA was identified in neoplastic lymphocytes from multiple organs by polymerase chain reaction and Southern blot analysis. Although the outcome of infection in this cheetah resembles that of FeLV infections in domestic cats, the transmission across an enclosure fence was unusual and may indicate a heightened susceptibility to infection in cheetahs. Caution should be exercised in holding and translocating cheetahs where contact could be made with FeLV-infected domestic, feral, or wild felids.     

Acute lymphoblastic leukemia hand-mirror cells with OKT 8 phenotype

Acute lymphoblastic leukemia with hand-mirror cells (ALL-HMC) was diagnosed in a 20-year old patient. Cytochemical investigations revealed a positive reaction for PAS and acid phosphatase. Lymphoid blast cells were studied with various monoclonal antibodies in order to determine their derivation and differentiation. The data obtained (positivity for Leu 9, OKT 11 and OKT 8) suggest that blast cells were of T lineage with OKT 8 phenotype. This report supports the phenotypic heterogeneity of ALL-HMC.     

Modulation of innate immune responses during human T-cell leukemia virus (HTLV-1) pathogenesis

Infection with the Human T-cell Leukemia virus type I (HTLV-1) retrovirus results in a number of diverse pathologies, including the aggressive, fatal T-cell malignancy adult T-cell leukemia (ATL) and the chronic, progressive neurologic disorder termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Worldwide, it is estimated there are 15-20 million HTLV-1-infected individuals; although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% of AC develops either ATL or HAM/TSP, but never both. Regardless of asymptomatic status or clinical outcome, HTLV-1 carriers are at high risk of opportunistic infection. The progression to pathological HTLV-1 disease is in part attributed to the failure of the innate and adaptive immune system to control virus spread. The innate immune response against retroviral infection requires recognition of viral pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRR) dependent pathways, leading to the induction of host antiviral and inflammatory responses. Recent studies have begun to characterize the interplay between HTLV-1 infection and the innate immune response and have identified distinct gene expression profiles in patients with ATL or HAM/TSP--upregulation of growth regulatory pathways in ATL and constitutive activation of antiviral and inflammatory pathways in HAM/STP. In this review, we provide an overview of the replicative lifecycle of HTLV-1 and the distinct pathologies associated with HTLV-1 infection. We also explore the innate immune mechanisms that respond to HTLV-1 infection, the strategies used by HTLV-1 to subvert these defenses and their contribution to HTLV-1-associated diseases.