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A Al-Katib

Publications and source records attributed to A Al-Katib.

At least 19 recordsLinked to original sources
PubMed2001

Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant.

We have identified 52 patients of follicular lymphoma (FL) with t(14;18)(q32;q21). Histologically, the lymphomas were placed into six groups according to their cellular composition and growth pattern. Chromosome analysis revealed that all cases but one had additional secondary chromosomal abnormalities. The most frequent numerical aberrations were gains of chromosomes 7 (38%), X (36%), 5 (15%), 12 (15%), 18/der(18)t(14;18) (25%), and 21 (15%). Structural abnormalities of chromosome 1 were seen in 19 tumors (36%) affecting both arms with breakpoints clustered at 1p36. Other structural abnormalities included partial deletions of 6q, 10q, and 13q. Breakpoint at 8q24 was seen in four cases. The chromosome aberrations were correlated with the morphological subtypes of follicular lymphoma. Gain of chromosome 7 appeared to be associated with follicular large cell lymphoma. The incidence of trisomy 5 and 12, and 13q- was higher in follicular lymphoma with aggressive histological features than in low-grade lymphoma. In addition, complexity of the karyotype and high degree of polyploidy increased with the grade. The most valuable cytogenetic markers in the t(14;18) lymphomas are those involving 8q24 which was found exclusively in the blastic/blastoid variant FL. Therefore, chromosome analysis in relation to histologic pattern of follicular lymphoma can provide additional information in predicting tumor evolution and transformation to a higher-grade malignancy.

Adult↗
PubMed1999

Neutron and photon clonogenic survival curves of two chemotherapy resistant human intermediate-grade non-Hodgkin lymphoma cell lines.

BACKGROUND: The potential role of neutron therapy in the management of intermediate-grade non-Hodgkin lymphoma (IGNHL) has not been examined because of the belief that the anticipated radiobiological effectiveness (RBE) would be uniformly very low. PURPOSE: To determine the fast neutron RBE for two chemotherapy-resistant IGNHL cell lines. METHODS AND MATERIALS: Conventional soft agar clonogenic survival curves following irradiation by 60Co and fast neutron were established for two IGNHL cell lines. These cell lines, WSU-DLCL2 and SK-DHL2B, were found in previous studies to be able to repair sublethal damage, and were also resistant to L-Pam and doxorubicin chemotherapy. RESULTS: When the surviving fraction after 2 Gy photon was chosen as the biological endpoint, the RBE for WSU-DLCL2 and SK-DHL2B measured 3.34 and 3.06. Similarly, when 10% survival was considered, the RBE for these two cell lines measured 2.54 and 2.59. The RBE, as measured by the ratios alpha neutron/alpha photon, for WSU-DLCL2, SK-DHL2B cell lines are 6.67 and 5.65, respectively. These results indicate that the RBE for these IGNHL cell lines is higher than the average RBE for cell lines of other histological types. CONCLUSION: Fast neutron irradiation may be of potential value in treating selected cases of IGNHL.

Cell Survival↗
PubMed1999

Expression of membrane-associated macrophage colony-stimulating factor (M-CSF) in Hodgkin's disease and other hematologic malignancies.

We have identified a membrane-bound form of M-CSF (m-M-CSF) from an established human leukemic J6-1 cell line. To further understand its biological significance, we studied the expression of this membrane-associated growth factor in the lymph nodes of lymphoma patients and bone marrow smears from patients with hematologic diseases by immunohistochemical staining using anti-M-CSF MAb. We detected a high incidence of m-M-CSF expression in 75% (9/12) of the lymph node sections from patients with Hodgkin's Disease (HD). The antigens were detected primarily in large clusters of mononuclear Hodgkin's cells and the extracellular matrix (EM) surrounding them. In one HD patient with abundant multinucleated Reed-Sternberg (R-S) cells, all of them were intensely stained with anti-M-CSF MAb. In non-Hodgkin's lymphomas (NHL), the incidence (17.6 %) of m-M-CSF expression was lower (3/17). Yet, no m-M-CSF antigens were detected in the lymph nodes from six cases of non-hematologic malignancies and other diseases. A high response also was detected in bone marrow smears obtained from patients with hematologic malignancies, which include myeloid leukemias (32.5%), lymphomas with bone marrow metastasis (50%) and myelodysplastic syndromes (MDS) (37.5 %). By comparison, only 6.8 % of bone marrow smears from non-malignant hematologic diseases and 2.7% of lymphoid leukemias showed positive staining with anti-M-CSF MAb. Our results showed that high expression of m-M-CSF antigens is linked to some types of lymphomas, especially HD. and myeloid leukemias, and may play a role in the development of these hematologic malignancies.

Adult↗
PubMed1999

A new tubulin polymerization inhibitor, auristatin PE, induces tumor regression in a human Waldenstrom's macroglobulinemia xenograft model.

Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease which remains incurable with current treatment protocols. We have previously established a permanent WM cell line, WSU-WM, which grows as a xenograft in severe combined immune deficient (SCID) mice. In this study, we investigated the anti-tumor effects of auristatin PE (a structural modification of the marine, shell-less mollusk peptide constituent dolastatin 10). WSU-WM cells were cultured in RPMI-1640 at a concentration of 2x10(5) cells/ml using 24-well plates. Auristatin PE or dolastatin 10 were added to triplicate wells and cell count and viability were assessed after 24, 48 and 72 h. Results showed that both agents were active against WSU-WM, and were able to induce complete growth inhibition at 100 pg/ml. The efficacy of these agents in vivo was evaluated using the WSU-WM SCID mouse xenograft model. Auristatin PE and dolastatin 10 were given i.v. via tail vein at 2.0 mg/kg and 0.2 mg/kg, respectively. The agents were given every second day for three injections which represent the maximum tolerated doses. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for auristatin PE and dolastatin 10 were 0%, 18 days, 2.83 and 67%, 2 days, 0.06, respectively. Based on these animal results, dolastatin 10 was inactive while auristatin PE was highly active. We therefore focused further investigation on auristatin PE to understand some of its mechanisms of action. Using two flow cytometry assays, propidium iodide for cell cycle analysis and 7-amino actinomycin D (7AAD) to detect apoptosis, we were able to demonstrate that auristatin PE at 10 pg/ml after 24 h arrested 50% of WSU-MW cells in G2M. Concomitantly, 31% of auristatin PE-treated cells entered apoptosis. By 72 h, greater than 75% of the cells became apoptotic. The activity of auristatin PE should be evaluated in other tumor types and in clinical trials.

Animals↗
PubMed1998

Synergistic interaction of selected marine animal anticancer drugs against human diffuse large cell lymphoma.

We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination with bryostatin 1 on a human diffuse large cell lymphoma line (WSU-DLCL2) in vitro and in vivo. WSU-DLCL2 cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis and apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ ml. Auristatin PE showed significant growth inhibition at concentrations as low as 10 pg/ml, while vincristine had a minimal effect at 50 pg/ml. Dolastatin 10, auristatin PE and vincristine-treated cultures, at 50 pg/ml, exhibited 11, 1.7; 45, 11.8%; and 39, 25% mitosis and apoptosis, respectively. In the WSU-DLCL2 SCID mouse xenograft model, the efficacy of these agents alone or in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C) and log10 kill for dolastatin 10, auristatin PE, vincristine and bryostatin 1 were 30%, 14 days and 1.4; 0.0%, 55 days and 5.5; 29.6%, 16 days and 1.6; and 39%, 7 days and 0.7, respectively. When given in combination, two out of five mice treated with auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 and vincristine + bryostatin 1 combinations were highly active but no cure was observed. We conclude that: (i) auristatin PE is more effective in this model than dolastatin 10, vincristine or bryostatin 1, (ii) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10, and (iii) there is a synergistic effect between these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be further explored clinically in the treatment of lymphoma.

Animals↗
PubMed1998

Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5'-NT and Bax/Bcl-2.

The activities of 2-chlorodeoxyadenosine (2-CdA) metabolizing enzymes, deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase (5'-NT) were measured in control and bryostatin 1 treated CLL cells using an EBV-negative WSU-CLL cell line. This cell line was established from a patient with CLL resistant to fludarabine. The results revealed a significant increase in dCK activity in bryostatin 1 treated cells at 48 and 72 h compared with the control. 5'-NT activity decreased significantly at 48 h. The ratio of dCK to 5'-NT activity was significantly increased in bryostatin 1 treated WSU-CLL cells after 48 h. WSU-CLL cells treated with bryostatin 1 exhibited an increase in the percentage of apoptotic and dead cells from control levels of 16% to 40%. This percentage was further increased to 67% following the addition of 11.2 microM 2-CdA to WSU-CLL cells pretreated with bryostatin 1. Results from Western blot analysis indicate that WSU-CLL cells express high levels of Bcl-2, Bcl-xL and c-myc, and a low level of Bax. p53 in untreated WSU-CLL cells is undetectable. WSU-CLL cells treated with bryostatin 1 showed a significant increase in the ratio of Bax to Bcl-2. To demonstrate that the bryostatin 1 mediated enhancement of 2-CdA efficacy was not restricted to in vitro cell culture, we have studied the tumor growth delay of WSU-CLL xenografts treated with placebo, bryostatin 1, 2-CdA, and bryostatin 1 followed by 2-CdA. SCID mice given bryostatin 1 at 75 microg x kg(-1) x d(-1) for 5 days followed by 30 mg x kg(-1) x d(-1) 2-CdA for 5 days in two cycles, had significantly improved tumor growth delay (P = 0.05). We conclude that bryostatin 1 is not only capable of inducing apoptosis by itself, but also sensitizes de novo resistant WSU-CLL cells to the chemo-therapeutic effects of 2-CdA. The bryostatin 1-induced increased ratio of dCK/5'-NT activity and an increased ratio of Bax/Bcl-2 are at least two mechanisms through which this natural compound is able to potentiate the anti-tumor activity of 2-CdA in otherwise resistant CLL cells.

5'-Nucleotidase↗
PubMed1998

An orthotopic model of human pancreatic cancer in severe combined immunodeficient mice: potential application for preclinical studies.

Pancreatic adenocarcinoma is one of the most incurable and least understood of all human cancers. It is the fourth leading cause of cancer-related mortality in males (after lung, prostate, and colon) and in females (after lung, breast, and colon) in the United States with <2-3% of patients surviving >5 years. In an attempt to search for more effective therapies for this disease, we report here, for the first time, an effective treatment, the combination of gemcitabine and auristatin-phenethylamine (PE), against an orthotopic implantation of a human pancreatic adenocarcinoma cell line (HPAC) in severe combined immunodeficient (SCID) mice. Tumor implantation was performed by injecting 100 microl of the HPAC cell suspension (1 x 10(6) cells) directly into the pancreas of 5-week-old SCID mice. After implantation, tumor formation was checked twice a week. All palpable tumors were detected within 21 days (100% take rate), and tumors were confirmed histologically to be pancreatic adenocarcinoma. For the subsequent efficacy trial, tumor-bearing SCID mice were randomized into four groups with five mice in each group. One served as a control, the second received gemcitabine alone (2.5 mg/kg/injection i.p.), the third received auristatin-PE alone (2.0 mg/kg/injection i.v.), and the fourth group received the combination of gemcitabine (i.p.) and auristatin-PE (1.5 mg/kg/injection i.v.). All animals were euthanized 7 days after the completion of their treatments, and the pancreases were resected. Histological examination revealed the tumors to be adenocarcinoma. The tumors were composed of diffuse sheets of cells interrupted by glandular spaces containing secretory material. Cytologically, the tumor cells were large, pleomorphic, and hyperchromatic. Many cells contained intracellular lumina containing mucin. Immunohistochemical studies showed strong p21WAF1 (p21) expression but no immunoreactivity with p53 and Her-2/neu antibodies. The mean pancreatic weight in the gemcitabine/auristatin-PE combination group was significantly (P = 0.014) lower (0.84 +/- 0.639 g) when compared with those of the control (2.91 +/- 1.19 g) and gemcitabine alone (1.84 +/- 0.796 g; P = 0.064) groups. In addition, the mean weight in the combination group approached statistical significance when compared with the auristatin-PE group alone (1.16 +/- 0.635 g; P = 0.028). We conclude that the combination of gemcitabine and auristatin-PE is an effective treatment against HPAC tumors in this xenograft model and more effective than treatment with either gemcitabine or auristatin-PE alone and could be considered for future animal studies with pancreas cancer and/or for human clinical trials.

Adenocarcinoma↗
PubMed1998

Successful treatment of human chronic lymphocytic leukemia xenografts with combination biological agents auristatin PE and bryostatin 1.

We tested the activity of dolastatin 10 (a natural product derived from the shell-less marine mollusk, Dolabella auricularia, a sea hare) and its structural modification, auristatin PE, alone and in combination with bryostatin 1 (a protein kinase C activator derived from the marine bryozoan Bugula neritina) on a human B-cell chronic lymphocytic leukemia cell line (WSU-CLL) and in a severe combined immune deficient (SCID) mouse xenograft model bearing this cell line. WSU-CLL cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis, and apoptosis were assessed after 24 h of incubation at 37 degrees C. Results showed that dolastatin 10 had no apparent inhibition of cell growth at concentrations less than 500 pg/ml. Auristatin PE, on the other hand, showed significant growth inhibition at concentrations as low as 50 pg/ml. Auristatin PE-treated cultures, at this concentration, exhibited 27 and 4.5% mitosis and apoptosis, respectively. Dolastatin 10, at the same concentration, did not exert any effect and was comparable with that of control cultures. In the WSU-CLL-SCID mouse xenograft model, the efficacy of these agents alone and in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C), and log10 kill for dolastatin 10, auristatin PE, and bryostatin 1 were 14%, 25 days, and 1.98; 2%, 25 days, and 1.98; 19%, 13 days, and 1.03, respectively. Auristatin-PE produced cure in three of five mice, whereas dolastatin 10 showed activity but no cures. When given in combination, auristatin PE + bryostatin 1-treated animals were all free of tumors (five of five) for 150 days and were considered cured. Dolastatin 10 + bryostatin 1-treated animals produced cure in only two of five mice. We conclude that: (a) auristatin-PE is more effective in this model than dolastatin 10; (b) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10; (c) there is a synergetic effect between these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be explored clinically in the treatment of CLL.

Animals↗
PubMed1997

The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines.

Flavopiridol is a novel, potent inhibitor of cyclin-dependent kinases (CDK). This synthetic flavone has been reported to exhibit antitumor activity in murine and human tumor cell lines in vitro and in vivo and is currently undergoing clinical phase I evaluation. In the present study, 1 Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), 1 EBV-transformed B-CLL cell line (I83CLL), and 1 non-EBV transformed B-CLL cell line (WSU-CLL) were used as targets. Treatment of the cells with flavopiridol (100 nmol/L to 400 nmol/L) led to a marked dose- and time-dependent inhibition of cell growth and survival as determined using trypan blue exclusion. Morphologic analysis showed characteristic apoptotic changes such as chromatin condensation and fragmentation, membrane blebbing, and formation of apoptotic bodies. Furthermore, quantitative assessment of apoptosis-associated DNA strand breaks by in situ TdT labeling showed that a significant number of flavopiridol-treated cells underwent apoptosis. These cellular effects were associated with a significant decrease in bcl-2 expression as observed by Northern and Western blotting. The results showed that flavopiridol downregulates bcl-2 mRNA and bcl-2 protein expression within 24 hours. Genistein and quercetin, two flavonoids that do not inhibit CDKs, did not affect bcl-2 expression. These data suggest an additional mechanism of action of this new flavone which might be useful as an agent in the treatment of chronic lymphoid malignancies.

Apoptosis↗
PubMed1997

Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis.

Basic fibroblast growth factor (bFGF) is a pleiotropic cytokine which has recently been shown to delay fludarabine-induced apoptosis in B cell chronic lymphocytic leukemia (B-CLL) cells. To investigate the potential mechanism of bFGF-mediated delay of apoptosis, two EBV-transformed B prolymphocytic cell lines (JVM-2, JVM-13), one EBV-transformed B-CLL cell line (I83CLL), and one non-EBV-transformed B-CLL cell line (WSU-CLL) were used as a model for chronic lymphoid malignancies. Viability data of cells treated with fludarabine alone or in combination with bFGF demonstrated that the addition of bFGF to the cells resulted in prolonged survival. Quantitative assessment of apoptosis-associated DNA strand breaks by in situ TdT labeling showed a protective effect of bFGF on fludarabine-treated cells. The potential effect of bFGF on bcl-2 mRNA expression was analyzed by Northern blotting. Stimulation with bFGF led to a time-dependent accumulation of bcl-2 specific mRNA in all three cell lines. Maximal levels of bcl-2 mRNA expression were detected after 8 h in JVM-2, and after 18 h in JVM-13 and I83CLL. Intracellular bcl-2 protein was also found to be increased upon bFGF stimulation in both EBV- and non-EBV-transformed cells. In addition, exposure of cells from three patients with B-CLL to bFGF showed an upregulation of bcl-2 protein after 4-8 h. Our data demonstrate that bFGF upregulates the expression of bcl-2 in these cells, suggesting that this increase in bcl-2 expression may play a role in the delay of fludarabine-induced apoptosis.

Apoptosis↗
PubMed1996

Clonal evolution of chronic lymphocytic leukemia to acute lymphoblastic leukemia.

A 38-year-old white man was diagnosed with B-cell chronic lymphocytic/prolymphocytic leukemia (CLL/PLL). The disease was unresponsive to a variety of chemotherapeutic regimes. One year after diagnosis, L3 blasts appeared in peripheral blood associated with more aggressive course. There was no change in the B-cell phenotype at that time, but cytogenetic analysis revealed the appearance of t(8;22)(q24;q11) and -21 superimposed on the original karyotype: 46,XY,+3,der(3)t(3;17)(p11;q12), t(11;14)(q13;q32),-17. These results indicate that the lymphoblastic transformation in our case emerged from the pre-existing B-lymphocytic clone.

Adult↗
PubMed1996

Role of ubiquitin carboxyl terminal hydrolase in the differentiation of human acute lymphoblastic leukemia cell line, Reh.

We have previously demonstrated that the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), induces differentiation of the acute lymphoblastic leukemia cell line, Reh, to a mature non-dividing state. Associated with this differentiation is the expression of ubiquitin carboxyl terminal hydrolase (UCH-L1). To investigate the role of UCH-L1 in TPA-induced Reh differentiation and apoptosis, molecular and chemical inhibition was used. Molecularly, a sequence-specific antisense oligodeoxynucleotide (AODN) directed against UCH-L1 transcript was used to inhibit the expression of the gene. In addition, its complementary sense oligodeoxynucleotide (SODN) was used to indicate the specificity of AODN action. Chemically, sodium borohydride (NaBH4), an inhibitor of UCH-L, was used to block the transcript product. TPA-induced changes in Reh cell growth and morphology, UCH-L1 protein expression, apoptosis contour, surface phenotype, and enzymatic profile were assessed in the presence or absence of NaBH4, AODN or SODN. As previously reported, TPA induced Reh cells to differentiate into monocytoid B lymphocytes and stimulated the apoptotic pathway. However, adding NaBH4 or AODN inhibited the TPA effect on all parameters measured except apoptosis. The sequence in which NaBH4 or AODN were added in relation to TPA did not affect any of the response variables measured. The use of SODN did not influence any of the parameters measured, indicating the specificity of the action. Thus, we conclude that UCH-L1 is involved in the differentiation process of the lymphoblastic leukemia cell line, Reh. Our data suggest that TPA-induced apoptosis of Reh cells has a separate pathway from that of differentiation or that UCH-L1 expression is independent of the apoptotic pathway.

Adolescent↗
PubMed1995

Clinical course and outcome of patients with Hodgkin's disease who progress after autologous transplantation.

Twenty-six of fifty-eight patients undergoing autologous bone marrow transplantation (autoBMT) or peripheral stem cell transplantation (PSCT) for Hodgkin's disease had progression of lymphoma (Hodgkin's or non-Hodgkin's) during the course of their follow-up. The majority of progressions, 81% (21/26), occurred within the first year of transplant; 12% (3/26) occurred at three years or more. Three patients developed a non-Hodgkin's lymphoma; all B-cell tumors primarily involving the gastrointestinal tract. The majority of patients (23/26) received at least one therapy after progression and 65% (17/26) of patients received multiple therapies. One patient who received a second BMT is alive without evidence of disease at 49 months following the second autologous BMT. The median survival for the entire group is 11 months. Forty-six percent (12/26) of patients survived more than one year and twenty-three percent (6/26) survived more than two years after disease progression. Post-progression survival is significantly related to time to progression.

Adolescent↗
PubMed1987

Multiparameter characterization of L3 leukemia cell populations.

Multiparameter analysis of 14 consecutive patients with L3 cell populations (FAB classification) in bone marrow showed consistently high mean cellular RNA content but heterogeneity with respect to percent cels in S- and G2M-phases of the cell cycle, cell surface phenotype, cytogenetic abnormalities, cellular DNA content, and nuclear activities of terminal deoxynucleotidyl transferase. Five of the 14 patients had the characteristic profile of L3 leukemia with high RNA content, a typical t(8;14) or t(8;22) translocation, low Tdt, B-cell surface phenotype, pseudodiploid modal number of chromosomes, high proliferation and normal DNA index. The remaining 9 patients had features thought to be unusual and they were very heterogeneous. Median survival time from time of diagnosis was 115 days with no patient alive after 474 days. The survival times exhibited excellent correlation with a parametric model assuming exponential distribution. Accordingly, the presence of abnormal DI predicted for decreased, and the presence of t(8;14) or pseudodiploidy was associated with increased survival rates. However, due to the small number of patients in this study, generally applicable conclusions should be drawn only from a collection of larger numbers of cases of this rare type of leukemia.

Adult↗
PubMed1986

Expression of immunoglobulin lambda light chain by the promyelocytic cell line HL-60.

The HL-60 cell line, established from a patient with acute promyelocytic leukemia, can be induced to undergo differentiation along the granulocyte or monocyte/macrophage line, depending on the particular inducer that is used. In this communication we provide evidence that HL-60 cells also have B lymphoid characteristics because by flow cytometry and clonal excess calculations, these cells are found to express immunoglobulin (Ig) lambda light chains on their surface. Furthermore, HL-60 cells contain poly(A)+ RNA that hybridizes with a DNA fragment encoding the constant region of Ig lambda chains and comigrates with lambda mRNA on RNA blots. Treatment of HL-60 cells with a phorbol ester that induces monocyte/macrophage differentiation resulted in the loss of surface Ig lambda chains and lambda RNA.

Antibodies, Neoplasm↗
PubMed1986

Cytofluorometric detection of chronic myelocytic leukemia supervening in a patient with chronic lymphocytic leukemia.

An 82-year-old woman with stage I chronic lymphocytic leukemia presented with systemic symptoms, minimal adenopathy, hepatosplenomegaly, and anemia five years after the initial diagnosis was made and while receiving no therapy. Her white blood cell count was 231,000/mm3 with an absolute neutrophil count of 164,360/mm3 and lymphocyte count of 43,890/mm3. Peripheral blood smear inspection revealed both increased mature lymphocytes and myeloid cells at all stages of maturation. Flow cytometric analysis of forward- and right-angle light scatters demonstrated the presence of two populations of cells, one lymphoid, bearing predominantly lambda light chain surface immunoglobulin and showing phenotypic characteristics of B cell chronic lymphocytic leukemia (HLA-DR-positive, BL-1-positive, BL-2-positive, BL-7-positive, Leu-1-positive, Leu-10-positive, BL-5-negative, BL-6-negative, and OKM1-negative), and another granulocytic population expressing phenotypic features compatible with myeloid lineage (HLA-DR-negative, Leu-1-negative, BL-1-negative, BL-2-negative, BL-7-negative, Leu-10-negative, BL-5-positive, BL-6-negative, OKM1-positive, and surface immunoglobulin-negative). All of the peripheral blood cell metaphases were Philadelphia chromosome-positive after 24 hours of culture, confirming the diagnosis of chronic myelocytic leukemia, whereas all of the Epstein-Barr virus-treated B lymphocyte metaphases showed a normal karyotype after two weeks of culture. In this patient, analysis of surface antigens and immunoglobulin fractions by flow cytometry proved to be useful in recognizing concomitantly expressed leukemic lineages. This approach allows the increasing recognition of the heterogeneity of leukemic populations.

Aged↗
PubMed1986

Common acute lymphoblastic leukemia characterized by four different DNA stemlines with heterogeneity in RNA content, antigen expression and sensitivity to chemotherapy.

Four subpopulations of cells with different DNA content were present in the bone marrow of a pediatric patient with acute lymphoblastic leukemia. Flow cytometry of DNA/RNA and DNA/surface antigen expression enabled the identification and characterization of diploid, hypertriploid, tetraploid and hypertetraploid leukemic cells. This was not appreciated by cytogenetic analysis, which identified only some tetraploid cells (3/20 metaphases). Common acute lymphoblastic leukemia antigen was expressed in all aneuploid and also on 17% of diploid cells. Quantitative CALLA expression was unrelated to ploidy and cell size. Cellular RNA content paralleled ploidy, i.e. the more aneuploid cells had increased RNA content and there was pronounced RNA heterogeneity within each DNA stemline. The different subclones showed almost identical stages of early B-cell differentiation. The early pre B-cell antigens BL1 and BL2 were expressed in approx. 80 and 60%, respectively, of aneuploid leukemic cells. Cytoplasmic immunoglobulin heavy chain was also present. Clonal excess of lambda light chain immunoglobulin on the cell surface was present on less than 10% of hypertriploid, tetraploid and hypertetraploid leukemic cells indicating differentiation of a subpopulation of aneuploid leukemic cells to mature B cells. This was not seen for any diploid cells. The heterogeneity of the different subpopulations was also evident in the differences in response to chemotherapy: the hypertriploid and hypertetraploid subpopulations were most sensitive to initial induction chemotherapy.

Aneuploidy↗