scholarly journals Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3259-3268 ◽  
Author(s):  
HG Ahuja ◽  
PS Jat ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Acute Leukemia ◽  
Protein Expression ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Monocytic Differentiation ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Rb Gene

Abstract The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

scholarly journals Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3259-3268 ◽  
Author(s):  
HG Ahuja ◽  
PS Jat ◽  
A Foti ◽  
M Bar-Eli ◽  
MJ Cline
Keyword(s):  
Acute Leukemia ◽  
Protein Expression ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Monocytic Differentiation ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Rb Gene

The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

scholarly journals The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1080-1085 ◽  
Author(s):  
CS Chen ◽  
JM Hilden ◽  
J Frestedt ◽  
PH Domer ◽  
R Moore ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cell Lines ◽  
Chromosomal Translocation ◽  
Leukemic Cell ◽  
Genomic Region ◽  
Acute Leukemias ◽  
Normal Tissues ◽  
Leukemic Cell Lines ◽  
A Minor ◽  
Chromosome 4Q21

The chromosomal translocation, t(4;11)(q21;q23), is the most common type of 11q23 chromosomal abnormality, being highly prevalent in infant acute leukemias and associated with a poor prognosis. The t(4;11) results in the fusion of an 11q23 gene (MLL, HRX, Htrx-1, or ALL-1) and a 4q21 gene (AF-4 or FEL). To further evaluate the 4q21 gene and its role in t(4;11) acute leukemia, we have cloned a 38-kb genomic region and mapped exons of the AF-4 gene. The 4q21 breakpoints in 19 cases of t(4;11) acute leukemia were analyzed by Southern analysis and pulsed- field gels. Seventeen of the 19 cases had breakpoints on chromosome 4q21 that were scattered in this 38 kb region. Expression of the AF-4 gene was studied in a total of 28 various nonhematopoietic, hematopoietic, and t(4;11) leukemic cell lines. The AF-4 gene was expressed in all cell lines as a major and a minor transcript. In addition to the normal transcripts, two fusion transcripts from the derivative 11 and derivative 4 chromosomes were identified in all t(4;11) cell lines except B1, which had only the der(11) transcript. These findings suggest that the breakpoints on 4q21 cluster over a broader area than do the breakpoints in the 11q23 gene, and that der(11) encodes the fusion RNA found consistently in leukemia cells.

scholarly journals The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1080-1085 ◽  
Author(s):  
CS Chen ◽  
JM Hilden ◽  
J Frestedt ◽  
PH Domer ◽  
R Moore ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cell Lines ◽  
Chromosomal Translocation ◽  
Leukemic Cell ◽  
Genomic Region ◽  
Acute Leukemias ◽  
Normal Tissues ◽  
Leukemic Cell Lines ◽  
A Minor ◽  
Chromosome 4Q21

Abstract The chromosomal translocation, t(4;11)(q21;q23), is the most common type of 11q23 chromosomal abnormality, being highly prevalent in infant acute leukemias and associated with a poor prognosis. The t(4;11) results in the fusion of an 11q23 gene (MLL, HRX, Htrx-1, or ALL-1) and a 4q21 gene (AF-4 or FEL). To further evaluate the 4q21 gene and its role in t(4;11) acute leukemia, we have cloned a 38-kb genomic region and mapped exons of the AF-4 gene. The 4q21 breakpoints in 19 cases of t(4;11) acute leukemia were analyzed by Southern analysis and pulsed- field gels. Seventeen of the 19 cases had breakpoints on chromosome 4q21 that were scattered in this 38 kb region. Expression of the AF-4 gene was studied in a total of 28 various nonhematopoietic, hematopoietic, and t(4;11) leukemic cell lines. The AF-4 gene was expressed in all cell lines as a major and a minor transcript. In addition to the normal transcripts, two fusion transcripts from the derivative 11 and derivative 4 chromosomes were identified in all t(4;11) cell lines except B1, which had only the der(11) transcript. These findings suggest that the breakpoints on 4q21 cluster over a broader area than do the breakpoints in the 11q23 gene, and that der(11) encodes the fusion RNA found consistently in leukemia cells.

scholarly journals EFFECT OF THAI SARAPHI FLOWER EXTRACTS ON WT1 AND BCR/ABL PROTEIN EXPRESSION IN LEUKEMIC CELL LINES

2017 ◽  
Vol 14 (2) ◽  
pp. 16-24 ◽  
Author(s):  
Rungkarn Sangkaruk ◽  
Methee Rungrojsakul ◽  
Singkome Tima ◽  
Songyot Anuchapreeda
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Leukemic Cell Lines

Cell lineage analysis of acute leukemia relapse uncovers the role of replication-rate heterogeneity and microsatellite instability

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 603-612 ◽  
Author(s):  
Liran I. Shlush ◽  
Noa Chapal-Ilani ◽  
Rivka Adar ◽  
Neta Pery ◽  
Yosef Maruvka ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Cell Subpopulation ◽  
Lymphoid Leukemia ◽  
High Throughput Method ◽  
Leukemia Relapse ◽  
Almost All ◽  
Lineage Trees

Abstract Human cancers display substantial intratumoral genetic heterogeneity, which facilitates tumor survival under changing microenvironmental conditions. Tumor substructure and its effect on disease progression and relapse are incompletely understood. In the present study, a high-throughput method that uses neutral somatic mutations accumulated in individual cells to reconstruct cell lineage trees was applied to hundreds of cells of human acute leukemia harvested from multiple patients at diagnosis and at relapse. The reconstructed cell lineage trees of patients with acute myeloid leukemia showed that leukemia cells at relapse were shallow (divide rarely) compared with cells at diagnosis and were closely related to their stem cell subpopulation, implying that in these instances relapse might have originated from rarely dividing stem cells. In contrast, among patients with acute lymphoid leukemia, no differences in cell depth were observed between diagnosis and relapse. In one case of chronic myeloid leukemia, at blast crisis, most of the cells at relapse were mismatch-repair deficient. In almost all leukemia cases, > 1 lineage was observed at relapse, indicating that diverse mechanisms can promote relapse in the same patient. In conclusion, diverse relapse mechanisms can be observed by systematic reconstruction of cell lineage trees of patients with leukemia.

scholarly journals Combinations of Drugs in the Treatment of Acute Leukæmias

1965 ◽  
Vol 58 (11P2) ◽  
pp. 988-990 ◽  
Author(s):  
C Gordon Zubrod
Keyword(s):  
Acute Leukemia ◽  
Childhood Leukemia ◽  
Task Force ◽  
Leukemic Cell ◽  
The United States ◽  
Leukemic Cells ◽  
Clinical Relapse ◽  
Acute Leukemias ◽  
Human Leukemic Cells ◽  
Childhood Acute Leukemia

In the United States, the Acute Leukemia Task Force has been studying ways to achieve chemical control over the acute leukemias. It was found that L1210 mouse leukemia is an excellent predictive model for childhood acute leukemia. Examination of the kinetics of cell generation led to the conclusions that a single cell could multiply to a lethal number of cells in a relatively short time, and that therapy must destroy every cell. Extension of these hypotheses to childhood leukemia has permitted estimates of generation time of human leukemic cells; the size of the leukemic cell population at clinical relapse and the fractional destruction of cells by individual drugs. By the use of combinations of antileukemic drugs complete cell destruction has been approached in a few patients with early leukemia.

scholarly journals Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 60-65 ◽  
Author(s):  
JT Holden ◽  
RB Geller ◽  
DC Farhi ◽  
HK Holland ◽  
LL Stempora ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Acute Leukemias ◽  
Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

DIGE-Based Proteomic Analysis Identifies NPM/B23 and Nucleolin C23 as Overexpressed Proteins In Relapsed /Refractory Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1711-1711
Author(s):  
Jian Da Hu ◽  
MinHui Lin ◽  
TingBo Liu ◽  
Jing Li ◽  
XinJi Chen ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Multidrug Resistance ◽  
Acute Leukemia ◽  
Western Blot ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Leukemia Cell ◽  
Leukemic Cell ◽  
Leukemic Cell Lines

Abstract Abstract 1711 Resistance to chemotherapy is a challenge in treatment of acute leukemia. Although the classic multidrug resistance (MDR) phenotype is often characterized by expression of drug efflux pump P-glycoprotein or by multidrug resistance-associated proteins, precise molecular mechanisms are largely unknown. To investigate novel protein changes involved in resistance mechanism, protein expression profiles between human myeloid leukemia HL-60 cell lines and adriamycin- resistant HL-60 cell lines (HL-60/ADR) was compared, which was based on a differential proteomic approach — 2 dimensional difference in gel Electrophoresis(2D-DIGE) followed by mass spectrometry (MALDI-TOF-MS) and complemented by western blot validation. 16 protein spots were identified as being differentially expressed (> 1.2 fold change and p≤ 0.05) between above two cell lines, among which 13 protein spots were identified as up-regulated and 3 as down-regulated in the HL-60/ ADR cell line. Proteins found to have higher abundance levels in the resistant HL-60/ADR cells included enzymes, proteins and oncogenes related to signal transduction, protein synthesis, cell growth regulation and metabolism. 3 lower abundance proteins are related to transcription. From 16 proteins, 2 proteins, nucleophosmin B23 (NPM B23)and nucleolin C23, were selected and verified in leukemia cell lines and primary leukemia samples by western blot. Compared to healthy control samples, which showed no expressions of these 2 proteins, leukemic cell lines revealed an obvious up-regulation of B23 and C23. Moreover, significantly higher expressions of B23 and C23 were found in 3 resistant leukemic cell lines, HL-60/ADR, K562/ADR and KG01 cells, compared to the parent HL-60 and K562 cells, and other leukemic cell lines. In de novo leukemia samples, 43.8%(35/80) expressed B23 and C23 proteins, 37.9% (22/58) AML and 59.1% (13/22) ALL respectively. Meanwhile, concomitant expression of B23 and C23, both positive or negative, was noted in 97%(79/80)patients. Over-expressions of B23 and C23 were observed in 68.8% relapased/refractory leukemia patients. With regard to treatment outcome,among those patients who achieved ongoing CR, fewer patients expressed 2 proteins, only 13.35% (7/52) AML and 46%(7/15) ALL respectively. It implicated that B23 and C23 may be involved in drug resistance and be useful in assessing treatment outcome and prognosis of leukemia. To a conclusion, these results provide a novel clue for the molecular mechanism of MDR and suggest that B23 and C23 are prognostic indicators for leukemia. Disclosures: No relevant conflicts of interest to declare.

The Novel Phospholipid Gemcitabine Conjugate KPC34 Has Activity In Acute Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1425-1425
Author(s):  
Timothy Pardee ◽  
Peter Alexander ◽  
Kristin Stadelman ◽  
Greg Kucera
Keyword(s):  
Bone Marrow ◽  
Survival Rate ◽  
Leukemic Cell ◽  
Leukemia Cells ◽  
P Value ◽  
Bone Marrow Stroma ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Marrow Stroma ◽  
Nm Range

Abstract Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are cancers of the bone marrow that in adults, occur mainly in the elderly. About 19,000 Americans develop these diseases annually and the 5 year survival rate is 30-40%. The prognosis for elderly patients is even worse with a 5 year survival rate of 10%. Treatment for AML and ALL involves induction chemotherapy using the deoxycytidine analog cytarabine followed by consolidation therapy or stem cell transplant. The major obstacle to long-term disease-free survival is relapse after treatment due to chemoresistance. Recurrent disease is much more difficult to treat successfully and elderly patients often have trouble tolerating repeated chemotherapy treatments. Chemoresistance can occur by several mechanisms including reduced activation of cytarabine via downregulated deoxycytidine kinase (dCK) levels or decreased uptake via lowered Equilibrative Nucleoside Transporter 1 (ENT-1) levels. Low expression of both dCK and ENT-1 correlate with poor prognosis in patients with acute leukemias. Another contributor to cytarabine resistance is the interaction of leukemia cells with bone marrow stroma. This interaction confers protection to leukemia cells from cytarabine by inhibiting apoptosis and ENT-1 function. Additionally, activation of NF-κβ by protein kinase C (PKC) promotes proliferation and inhibits apoptosis in AML. Increased expression of PKC isoforms α, β1, and β2 have been detected in both AML and ALL and promote leukemic proliferation and survival by activation of ERK and the anti-apoptotic protein BCL-2. The development of novel therapeutic agents or modifying existing drugs may be able to overcome chemoresistance in AML and ALL and improve clinical outcomes. KPC34 is a novel phospholipid conjugate of the deoxycytidine analog gemcitabine. Gemcitabine acts similarly to cytarabine and is administered IV to treat various tumors and lymphomas, but is rarely used for leukemias. Compared to cytarabine, gemcitabine treatment inhibits DNA replication more effectively, prevents repair of damaged DNA, and uniquely inhibits ribonucleotide reductase. KPC34's novel properties result in improved pharmacokinetics compared to gemcitabine and may be able to overcome leukemic chemoresistance to cytarabine by bypassing the need for ENT-1 uptake and dCK activation. In addition, KPC34 can be administered orally, is predicted to cross the blood-brain barrier, allowing it to target CNS-infiltrating leukemias. Finally, KPC34’s lipid moiety is predicted to inhibit the activity of PKC. In order to determine if KPC34 has activity against acute leukemias we tested it against a variety of human and murine leukemic cell lines in vitro. KPC34 was highly cytotoxic to with IC50s in the nM range. The mean IC50 was 45.92 nM (range from 7.39-175.6 nM). Exposure of leukemia cells to KPC34 resulted in the induction of apoptosis as assessed by annexin V and PI assays. Human leukemic cell lines treated with KPC34 had dose-dependent reduction of colony formation, where normal donor hematopoietic stem cells did not. To test the ability of KPC34 to overcome stroma-mediated chemoresistance, SUPB15 cells were incubated in the presence or absence of a bone marrow stroma cell line for 48 hrs. The cells were then treated with 10 nM cytarabine or KPC-34. No significant difference was seen between either treatment without stroma, while KPC34 significantly increased apoptosis in the presence of stroma (p value ≤ 0.001, by Student’s t test). In order to assess the activity of KPC34 in vivo, we injected C57/BL6 mice with a syngeneic, murine Ph+ pre-B cell ALL, luciferase expressing cell line. When engraftment was established by bioluminescence imaging, mice were treated with 25 mg/kg KPC34 or water by oral gavage on days 1, 4 and 7. Treatment resulted in a significant prolongation of survival with treated mice having a median survival of 26 days compared to 13 days for controls (p value of 0.0042, by log-rank test). These data demonstrate the activity of KPC34 in multiple preclinical models of leukemia and support its continued translation to the clinic. Disclosures: Kucera: Wake Forest Baptist Health: KPC 34 Patent, KPC 34 Patent Patents & Royalties.

Sign in / Sign up

Export Citation Format

Share Document