B-cell Prolymphocytic Leukemia Research Articles

High expression of the multidrug resistance-associated protein (MRP) in chronic and prolymphocytic leukaemia.

The expression of the multidrug resistance-associated protein (MRP), a new glycoprotein involved in drug resistance, was investigated in tumour samples from 80 patients with chronic B-cell malignancies by a quantitative RNase protection assay. In B-cell chronic lymphocytic leukaemia (B-CLL) (n = 32), either treated (n = 18) or untreated (n = 14), a high percentage of patients (20/32: 63%) had relatively high expression levels of the MRP gene (25U or more). In addition, hyperexpression of the MRP gene was demonstrated in 4/10 (40%) untreated patients with B-cell prolymphocytic leukaemia (B-PLL). In contrast, low MRP mRNA expression levels were detected in hairy cell leukaemia (n = 7), non-Hodgkin's lymphoma (n = 13) and multiple myeloma (n = 18). Statistical analysis of MRP expression in untreated CLL (mean +/- SD 29.2 +/- 18.5 U) versus treated CLL (mean +/- SD 26.7 +/- 13.7 U) did not show significant differences in MRP expression between the two groups. Southern blot analysis did not reveal amplification of the MRP gene in the leukaemia samples with elevated MRP mRNA levels. We conclude that B-PLL and B-CLL frequently display high MRP expression and that this hyperexpression is probably due to transcriptional activation and/or increased mRNA stability.

Promace day 1/MOPP day 8 chemotherapy for prolymphocytic leukemia: A case report of prolonged survival

The treatment result of a case of de novo B-cell prolymphocytic leukemia (B-PLL) is described. The diagnosis was established with histologic, ultrastructural and immunologic studies. The patient was treated with chemotherapy using a total of seven cycles of ProMACE Day 1/MOPP Day 8 lymphoma regimen. Complete remission was achieved after 5 cycles of chemotherapy. The patient remains disease free after a 7-year follow up. This is the first case of PLL being treated with such a regimen and the only case reported achieved such prolonged survival. Results of other treatment modalities are reviewed.

BCL2 translocations in leukemias of mature B cells

Although translocations of the BCL2 gene are frequent in B-cell non- Hodgkin's lymphomas (B-NHL) the incidence, nature, and prognostic significance of similar translocations in the phenotypically related chronic leukemias of mature B cells are unknown. Therefore, we examined 170 cases of B-cell chronic lymphocytic leukemia (B-CLL), 7 cases of B- cell prolymphocytic leukemia (B-PLL), 25 cases of hairy cell leukemia (HCL) and 22 cases of splenic lymphoma with villous lymphocytes (SLVL) with defined cytogenetic abnormalities by DNA blot using both 5′ and 3′ BCL2 probes to search for rearrangement of the BCL2 locus. Translocation t(14;18) (q32.3;q21.3) was detected cytogenetically in 3 cases of B-CLL. All had breakpoints in the 3′ region of BCL2, mapping between the major breakpoint region (MBR) and the minor cluster region (mcr), the breakpoint clusters commonly detected in B-NHL. In 2 of the 3 cases, the breakpoint within BCL2 was mapped to a 1.0-kb EcoRI- HindIII fragment indicating a clustering of breakpoints. Two cases of B- CLL had cytogenetically detectable t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). Both had rearranged the 5′ region of the BCL2 gene to the corresponding lg light-chain gene. Molecular cloning of the t(18;22)(q21.3;q11) showed that the translocation disrupted the BCL2 promoter region and the first untranslated BCL2 exon. Nevertheless, high levels of BCL2 protein were seen in this case. Only 2 other cases in whom cytogenetic analysis was not successful showed rearrangement of the 5′ region of BCL2, an overall incidence of 2.3%. No cases of B-PLL, HCL, or SLVL showed either 5′ or 3′ BCL2 rearrangement. These data confirm the cytogenetic observations that translocations involving the BCL2 locus in all forms of leukemia of mature B cells are rare, and limited to a minor subset of B-CLL. BCL2 translocations in B-CLL involve hot spots of recombination of both the 5′ and 3′ regions of the BCL2 gene, which are distinct from those commonly seen in B-NHL, suggesting distinct pathogenic mechanisms.

BCL2 Translocations in Leukemias of Mature B Cells

Although translocations of the BCL2 gene are frequent in B-cell non-Hodgkin's lymphomas (B-NHL) the incidence, nature, and prognostic significance of similar translocations in the phenotypically related chronic leukemias of mature B cells are unknown. Therefore, we examined 170 cases of B-cell chronic lymphocytic leukemia (B-CLL), 7 cases of B-cell prolymphocytic leukemia (B-PLL), 25 cases of hairy cell leukemia (HCL) and 22 cases of splenic lymphoma with villous lymphocytes (SLVL) with defined cytogenetic abnormalities by DNA blot using both 5' and 3' BCL2 probes to search for rearrangement of the BCL2 locus. Translocation t(14;18) (q32.3;q21.3) was detected cytogenetically in 3 cases of B-CLL. All had breakpoints in the 3' region of BCL2, mapping between the major breakpoint region (MBR) and the minor cluster region (mcr), the breakpoint clusters commonly detected in B-NHL. In 2 of the 3 cases, the breakpoint within BCL2 was mapped to a 1.0-kb EcoRI-HindIII fragment indicating a clustering of breakpoints. Two cases of B-CLL had cytogenetically detectable t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). Both had rearranged the 5' region of the BCL2 gene to the corresponding lg light-chain gene. Molecular cloning of the t(18;22)(q21.3;q11) showed that the translocation disrupted the BCL2 promoter region and the first untranslated BCL2 exon. Nevertheless, high levels of BCL2 protein were seen in this case. Only 2 other cases in whom cytogenetic analysis was not successful showed rearrangement of the 5' region of BCL2, an overall incidence of 2.3%. No cases of B-PLL, HCL, or SLVL showed either 5' or 3' BCL2 rearrangement. These data confirm the cytogenetic observations that translocations involving the BCL2 locus in all forms of leukemia of mature B cells are rare, and limited to a minor subset of B-CLL. BCL2 translocations in B-CLL involve hot spots of recombination of both the 5' and 3' regions of the BCL2 gene, which are distinct from those commonly seen in B-NHL, suggesting distinct pathogenic mechanisms.

Immunophenotypic and idiotypic characterisation of the leukaemic B-cells from patients with prolymphocytic leukaemia: Evidence for a selective expression of immunoglobulin variable region (IGV) gene products

B-cell prolymphocytic leukaemia (B-PLL) is a rare chronic lymphoproliferative disease characterised by a massive splenomegaly associated with a mild or no lymphadenopathy and a high leukocyte count, mostly representing prolymphocytic features. We have studied membrane expression of certain Ig V K and V II gene products in five patients with B-PLL using a panel of monoclonal anti-subgroup and anti-cross-reactive idiotype (CRI) antibodies. Membrane expression of leukocyte-associated markers has also been investigated. The leukaemic cells from four patients expressed V KIII and V KIIIb subgroup and sub-subgroup kappa light chains. The V KIIIb and V HI-associated CRI identified by the monoclonal antibodies (MoAb) 17–109 and G8 were co-expressed in one patient. No B-cells from the patients expressed the V HIII-associated CRI. The same pattern of CRI expression was observed in a serum paraprotein collected from one of the patients. These results suggest a biased selection for the IG V KIII and V KIIIb light chains in B-PLL.

Telomeric associations in a patient with B‐cell prolymphocytic leukaemia

Telomeric associations were determined in bone marrow preparations from a patient with B-cell prolymphocytic leukaemia and a clonal isochromosome of the long arm of chromosome 17. Thirteen associations involved 16 chromosome arms, with preferential involvement of the short arm of chromosome 19 and the long arm of 17.

Ranimustineが著効を奏したB-cell prolymphocytic leukemiaの1例

Ranimustineが著効を奏したB-cell prolymphocytic leukemiaの1例

Leukemic B-cell Colony Formation in Patients with B-cell Prolymphocytic Leukemia

Leukemic B-cell Colony Formation in Patients with B-cell Prolymphocytic Leukemia

The Expression of CD22 (Leu 14) and CD11c (LeuM5) in Chronic Lymphoproliferative Disorders Using Two-Color Flow Cytometric Analysis

The monoclonal antibodies (MoAbs) CD22 and CD11c recognize B-lymphocyte- and monocyte-associated antigens, respectively. Reports indicate that when these two MoAbs co-express, they represent a unique marker for hairy cell leukemia (HCL) although neither is specific for that disease. The authors evaluated the expression and diagnostic utility of CD22 and CD11C in specimens from 26 normal subjects, 29 patients, with various nonlymphoproliferative disorders (NLPDs), and 75 patients with different types of chronic lymphoproliferative disorders (CLDs) using two-color flow cytometric analysis of peripheral blood lymphocytes. Lymphocytes co-expressed CD22 and CD11c in less than or equal to 3% of the normal subjects and in less than or equal to 6% of the patients with NLPDs. These markers were expressed in greater than 10% of the lymphocytes of 46% (32/69) of the patients with B-cell CLDs: B-cell chronic-lymphocytic leukemia, 9/41; B-cell non-Hodgkin's lymphoma, 8/14; HCL, 11/11; B-cell lymphoproliferative disorder (NOS), 1/2; and B-cell prolymphocytic leukemia, 1/1. None (0/6) of the lymphocytes of patients with T-cell CLDs expressed greater than 10% CD22-positive (CD22+) or CD11c-positive (CD11c+) cells. The HCL cases demonstrated a unique CD22+CD11c+ fluorescence histogram pattern, distinct from other lymphoproliferative disorders, that was characterized by uniformly intense CD11c and CD22 fluorescence. Differences in the expression of the CD22+CD11C- and CD22+CD11C+ phenotypes between diagnostic groups were found, most notable was a paucity of CD22+CD11c+ cells in lymphocytes of patients with HCL. CD22 also had more variable expression than CD19 and HLA-DR in the cases of B-cell CLD. This study demonstrates that the CD22+CD11c+ phenotype is not unique to HCL but is a consistent feature of that disorder and that the immunofluorescence pattern of co-expression in HCL is diagnostically useful.

B-ly-7, a monoclonal antibody reactive with hairy cell leukemia, also defines an activation antigen on normal CD8+ T cells [see comments

We undertook a study to determine the specificity of the monoclonal antibody, B-ly-7, for hairy cell leukemia (HCL) by examining the expression in 150 samples from B-cell lymphoproliferative diseases as well as screening for reactivity in a number of other hematologic malignancies. Within the B-cell lineage we found that the expression of B-ly-7 was highly specific for HCL and reacted with all 28 cases examined, as well as with 3 of 9 cases of a variant form of HCL. Cells of other closely related B-cell disorders, prolymphocytic leukemia, and splenic lymphoma with villous lymphocytes were negative. Investigation of the peripheral blood and bone marrow of patients with HCL before and after treatment with alpha-interferon or deoxycoformycin suggests that B-ly-7 may be useful in the assessment of minimal disease after therapy. In addition to HCL, we found that B-ly-7 was positive with cells of three mature, CD4+ T-cell malignancies. In view of the reactivity with malignancies of activated B and T cells, we searched for the expression of B-ly-7 on activated, normal B and T cells and found that B-ly-7 reacted specifically with activated normal peripheral blood CD8+ T cells. B-ly-7 has a number of applications, including the precise classification of mature B-cell neoplasia and the diagnosis HCL and its assessment after treatment. In addition, B-ly-7 recognizes a small subset of T-cell disorders. Its expression on these malignancies and on in vitro activated peripheral blood CD8+ T cells suggests that B- ly-7 detects a lymphocyte activation antigen.

B-ly-7, a Monoclonal Antibody Reactive With Hairy Cell Leukemia, Also Defines an Activation Antigen on Normal CD8+ T Cells

We undertook a study to determine the specificity of the monoclonal antibody, B-ly-7, for hairy cell leukemia (HCL) by examining the expression in 150 samples from B-cell lymphoproliferative diseases as well as screening for reactivity in a number of other hematologic malignancies. Within the B-cell lineage we found that the expression of B-ly-7 was highly specific for HCL and reacted with all 28 cases examined, as well as with 3 of 9 cases of a variant form of HCL. Cells of other closely related B-cell disorders, prolymphocytic leukemia, and splenic lymphoma with villous lymphocytes were negative. Investigation of the peripheral blood and bone marrow of patients with HCL before and after treatment with alpha-interferon or deoxycoformycin suggests that B-ly-7 may be useful in the assessment of minimal disease after therapy. In addition to HCL, we found that B-ly-7 was positive with cells of three mature, CD4+ T-cell malignancies. In view of the reactivity with malignancies of activated B and T cells, we searched for the expression of B-ly-7 on activated, normal B and T cells and found that B-ly-7 reacted specifically with activated normal peripheral blood CD8+ T cells. B-ly-7 has a number of applications, including the precise classification of mature B-cell neoplasia and the diagnosis HCL and its assessment after treatment. In addition, B-ly-7 recognizes a small subset of T-cell disorders. Its expression on these malignancies and on in vitro activated peripheral blood CD8+ T cells suggests that B-ly-7 detects a lymphocyte activation antigen.

Expression of mdr1 and mdr3 Multidrug-resistance Genes in Human Acute and Chronic Leukemias and Association With Stimulation of Drug Accumulation by Cyclosporine

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1-encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.

Nucleotide sequence of an immunoglobulin D-J gene fusion from a B-cell prolymphocytic leukaemia.

Nucleotide sequence of an immunoglobulin D-J gene fusion from a B-cell prolymphocytic leukaemia.

Oncogenes in chronic lymphocytic leukemia

Oncogenes, in the context of retroviruses, are a common cause of leukemia in animals. Recently, activation of cellular oncogenes has been shown to be associated with leukemia in humans. Relatively few studies of oncogene activation in chronic lymphocytic leukemia (CLL) have been reported. In most instances, rearrangement of oncogenes has not been detected. Exceptions include the bcl-1 oncogene in B-cell prolymphocytic leukemia, the tcl-1 oncogene in T-cell CLL, the Hu- ets-1 and Hu- ets-2 oncogenes in small cell lymphocytic lymphoma and c- myc in a Sezary cell leukemia cell/line. Overall, it appears that oncogene abnormalities are less common in CLL than in other leukemias. The reason for it is uncertain and may relate to the relatively few cases evaluated. Alternatively, novel mechanisms of oncogene involvement or gene other than oncogenes may be important in the etiology or pathogenesis of CLL.

The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia

A series of 55 patients with B-cell chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) was studied in order to investigate the evolution of prolymphocytoid transformation of CLL. Peripheral blood films were assessed for the percentages of prolymphocytes (%PROL) during a followup period of 2 months to 24 years. The majority of patients with typical CLL (less than or equal to 10% PROL) had minor variations or transient increases in %PROL throughout the course of the disease, but in one third of them a steady rise in the proportion of these cells was documented. Patients presenting with 11-55% PROL, referred to as CLL/PL, exhibited three patterns of evolution: half of them showed stability of the PROL counts, one third had unsustained increases in the %PROL and 18% showed definite progression to a PLL-like blood picture. Patients diagnosed as PLL (greater than 55% PROL) had maintained a high %PROL during the period of observation. Serial marker studies in some CLL and CLL/PL cases showed that the percentage of M-rosettes and the intensity of SmIg remained at the same initial levels in all but two cases. These two cases in the CLL/PL group showed a significant decrease in the percentage of M-rosettes and stronger SmIg staining associated with progressive prolymphocytoid transformation. Patients with CLL and CLL/PL who had a sustained rise in the %PROL responded poorly to treatment compared with those with stable disease.

Del(3)(p13) in B-prolymphocytic leukemia—A new nonrandom chromosomal aberration possibly related to the c- ras oncogene

Cytogenetic analysis was performed on the leukemic cells from two patients with B-prolymphocytic leukemia. Both patients had del(3)(p13) chromosomal abnormality, as well as other clonal aberrations. Del(3p) was previously reported in one case of B-cell prolymphocytic leukemia, and is known to be a specific aberration in small-cell carcinoma of the lung. In B-cell prolymphocytic leukemia, as in other B-lymphocytic leukemias/lymphomas, the karyotype often involves chromosomes #3, #6, #11, and #12. All of these chromosomes are suggested sites for the c-ras oncogene family.

Possible Specific Chromosome Change in Prolymphocytic Leukemia

The chromosomes of unstimulated and stimulated blood lymphocytes from 5 cases with B-cell prolymphocytic leukemia (PLL) were examined following the use of polyclonal B-cell activators (PBA). Banding techniques revealed a common and specific chromosome abnormality to be present in each of the cases, which was due to a translocation between chromosomes 6 and 12 (t(6;12)(q15;p13]. The fact that this specific chromosome change has not been reported in other lymphoproliferative disorders may indicate that PLL is a distinct clinical entity and different from other lymphoproliferative disorders, whether it occurs de novo or complicates chronic lymphocytic leukemia (CLL).

Possible specific chromosome change in prolymphocytic leukemia

The chromosomes of unstimulated and stimulated blood lymphocytes from 5 cases with B-cell prolymphocytic leukemia (PLL) were examined following the use of polyclonal B-cell activators (PBA). Banding techniques revealed a common and specific chromosome abnormality to be present in each of the cases, which was due to a translocation between chromosomes 6 and 12 (t(6;12)(q15;p13]. The fact that this specific chromosome change has not been reported in other lymphoproliferative disorders may indicate that PLL is a distinct clinical entity and different from other lymphoproliferative disorders, whether it occurs de novo or complicates chronic lymphocytic leukemia (CLL).

Chromosome abnormalities in B-cell prolymphocytic leukemia: A study of nine cases

Chromosome abnormalities were demonstrated in 50–100% of Giemsa-banded metaphases from nine cases of B-cell prolymphocytic leukemia (B-PLL). Mitoses were obtained with pokeweed mitogen following pretreatment of peripheral blood (PB) prolymphocytes with neuraminidase-galactose oxidase. Chromosome 14 was abnormal in eight of the nine cases: a marker 14q+, with breakpoint at band q32 in seven and trisomy 14 in one. In four cases the abnormal No. 14 was one of several primary abnormalities and in four others it was seen in secondary clones. The origin of the translocated material was unknown in three cases, in two it resulted from t(11;14), later becoming t(11;14;21) in one of them, t(1;14) in another, progressing later to t(1;14;17); in yet another patient, the 14q was the result of a complex rearrangement t(6;14;17). Abnormalities of chromosome 6 were seen in six cases; 6q− as the primary abnormality in three; trisomy 6 was part of secondary changes in one case. Structural abnormalities of chromosome 1 were seen in six cases: 1q− in four (in one as the only abnormality), 1q+ in one case, and 1p− in another, both in the main clone. Trisomy 12 was demonstrated in three cases but not as the primary change. Spleen cells in two patients showed a higher frequency of abnormalities than in the PB, supporting the concept of the spleen being the organ primarily involved in B-PLL. Evidence of karyotypic evolution was demonstrated in six patients, in some clearly associated with clinical progression of the disease. The type and frequency of the abnormalities observed in B-PLL resemble those seen in non-Hodgkin's lymphomas and suggest major differences from B-CLL, although a relationship with the latter can not be completely ruled out at present.

4 Clinical patterns in B lymphoid malignancy

B-cell prolymphocytic leukaemia (B-PLL) is a rare chronic lymphoproliferative disease characterised by a massive splenomegaly associated with a mild or no lymphadenopathy and a high leukocyte count, mostly representing prolymphocytic features. We have studied membrane expression of certain Ig VK and VII gene products in five patients with B-PLL using a panel of monoclonal anti-subgroup and anti-cross-reactive idiotype (CRI) antibodies. Membrane expression of leukocyte-associated markers has also been investigated. The leukaemic cells from four patients expressed VKIII and VKIIIb subgroup and sub-subgroup kappa light chains. The VKIIIb and VHI-associated CRI identified by the monoclonal antibodies (MoAb) 17–109 and G8 were co-expressed in one patient. No B-cells from the patients expressed the VHIII-associated CRI. The same pattern of CRI expression was observed in a serum paraprotein collected from one of the patients. These results suggest a biased selection for the IG VKIII and VKIIIb light chains in B-PLL.