scholarly journals Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 1005-1012 ◽  
Author(s):  
T Skorski ◽  
M Nieborowska-Skorska ◽  
P Wlodarski ◽  
G Zon ◽  
RV Iozzo ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Therapeutic Potential ◽  
Blast Crisis ◽  
Scid Mice ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Mouse Tissue ◽  
Antisense Oligodeoxynucleotide ◽  
Primary Cells

Abstract The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c- myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.

scholarly journals Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 1005-1012 ◽  
Author(s):  
T Skorski ◽  
M Nieborowska-Skorska ◽  
P Wlodarski ◽  
G Zon ◽  
RV Iozzo ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Therapeutic Potential ◽  
Blast Crisis ◽  
Scid Mice ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Mouse Tissue ◽  
Antisense Oligodeoxynucleotide ◽  
Primary Cells

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c- myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.

scholarly journals Production of Colony-stimulating Factor by Malignant Leukocytes

Blood ◽  
1974 ◽  
Vol 43 (5) ◽  
pp. 749-756 ◽  
Author(s):  
David W. Golde ◽  
Belina Rothman ◽  
Martin J. Cline
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Csf Production

Abstract There is considerable evidence supporting a role for colony-stimulating factor (CSF) as a humoral regulator of leukopoiesis. Data on CSF levels in the serum and urine of patients with leukemia and on the in vitro responsiveness of leukemic cells to CSF have suggested a basis for considering leukemia as a primary disorder of leukopoietic regulation. We examined the question of leukemic cell production of CSF. Conditioned medium from cultured leukemic cells was tested for colony-stimulating activity against normal human bone marrow using a two-layer agar colony assay technique. The cells from patients with acute myelogenous leukemia and a patient with chronic myelogenous leukemia in blast crisis did not elaborate CSF nor did acute lymphocytic leukemia cells. CSF production was documented with cells obtained from patients with chronic myelogenous leukemia in the chronic phase and two patients with acute myelomonocytic leukemia. In acute leukemia the cellular production of CSF correlated closely with morphologic and functional maturation along the monocyte-macrophage line. Evidence was obtained that the adherent cells within the leukemic population were primarily responsible for CSF production. We interpret these data to indicate that neoplastic hematopoietic cells may produce CSF in relation to their capacity for mononuclear leukocyte differentiation.

scholarly journals Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3449-3456 ◽  
Author(s):  
C Wada ◽  
S Shionoya ◽  
Y Fujino ◽  
H Tokuhiro ◽  
T Akahoshi ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Genetic Event ◽  
Familial Predisposition ◽  
Somatic Instability

Abstract Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

Effects of sCD23 on proliferation of leukemic cells from a patient with chronic myelogenous leukemia during blast crisis

1993 ◽  
Vol 44 (1) ◽  
pp. 60-62 ◽  
Author(s):  
F. Morel ◽  
V. Delwail ◽  
A. Brizard ◽  
A. Meseri ◽  
F. Guilhot ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

scholarly journals Cytogentics of fibroblastic colonies in Ph1-positive chronic myelogenous leukemia

Blood ◽  
1978 ◽  
Vol 51 (6) ◽  
pp. 1039-1044 ◽  
Author(s):  
BR Greenberg ◽  
FD Wilson ◽  
L Woo ◽  
HM Jenks
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Blast Crisis ◽  
Marker Chromosome ◽  
Malignant Potential ◽  
Myelogenous Leukemia ◽  
Reactive Component

Abstract The cytogenetic status of bone marrow stromal elements obtained from six patients with Ph1-positive chronic myelogenous leukemia (CML), two in blast crisis, was studied in vitro utilizing the potential of marrow to form surface-adherent colonies morphologically compatible with mesenchymal elements. We demonstrated the absence of both the marker chromosome and other chromosomal abnormalities in all the fibroblastic colonies studied, indicating that the progenitors of such colonies (plaque-forming units in culture, PFU-C) are not closely related to hematopoietic elements including macrophages. This supports previous reports suggesting that the stromal elements in myelofibrosis associated with CML are not derived from the primary Ph1-positive malignant clone but represent a stromal reactive component of benign or independent malignant potential.

scholarly journals Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3449-3456 ◽  
Author(s):  
C Wada ◽  
S Shionoya ◽  
Y Fujino ◽  
H Tokuhiro ◽  
T Akahoshi ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Genetic Event ◽  
Familial Predisposition ◽  
Somatic Instability

Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

scholarly journals Leukemia-associated antigens in ALL

Blood ◽  
1979 ◽  
Vol 54 (6) ◽  
pp. 1240-1248 ◽  
Author(s):  
JM Pesando ◽  
J Ritz ◽  
H Lazarus ◽  
SB Costello ◽  
S Sallan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Periodic Acid ◽  
Hematologic Malignancies ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Periodic Acid Schiff

A cytotoxic common ALL antiserum (CALLA) specific for leukemic cells of most patients with non-T-cel- acute lymphoblastic leukemia (ALL) and of some patients with chronic myelogenous leukemia (CML) in blast crisis has been reproducibly prepared using cell lines for absorption. CALLA reacts with leukemic cells of 110 of 134 patients (82%) with non-T-cell ALL; 1 of 71 (1%) patients with acute myelogenous leukemia (AML); 2 of 7 patients (29%) with chronic myelogenous leukemia in blast crisis; 7 of 92 patients (8%) with other hematologic malignancies; and with the leukemic cell lines Laz 221 and NALM-1. It does not react with the normal hematopoietic cells, B- or T-cell lines, or cells from 26 patients with T-cell ALL that were tested. CALLA reactivity and periodic acid Schiff (PAS) staining correlate poorly, with CALLA reacting with cells from 86% (64 of 74) of patients with PAS-positive and 76% (29 of 38) of those with PAS-negative non-T-cell ALL. In these patients, CALLA reacts with cells from 89% of those under age 12 (78 of 88); 74% of those aged 12--20 (20 of 27); and 58% of those over 20 (11 of 19). Using only CALLA and antisera specific for Ia-like and T-cell antigens, we can now distinguish most cases of ALL from AML and other hematologic malignancies.

scholarly journals Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 600-605 ◽  
Author(s):  
DS Snyder ◽  
Y Wu ◽  
JL Wang ◽  
JJ Rossi ◽  
P Swiderski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Cell Biology ◽  
Fusion Gene ◽  
Therapeutic Potential ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
A Cell

Abstract The bcr-abl fusion gene is the molecular counterpart of the Philadelphia chromosome (Ph1) and is directly involved in the pathogenesis of Ph1+ leukemia. Inhibition of bcr-abl gene expression may have profound effects on the cell biology of Ph1+ cells, as recent experiments with antisense oligonucleotides have shown. In this study we have designed and synthesized a unique ribozyme that is directed against bcr-abl mRNA. The ribozyme cleaved bcr-abl mRNA in a cell-free in vitro system. A DNA-RNA hybrid ribozyme was then incorporated into a liposome vector and transfected into EM-2 cells, a cell line derived from a patient with blast crisis of chronic myelogenous leukemia. The ribozyme decreased levels of detectable bcr-abl mRNA in these cells, inhibited expression of the bcr-abl gene product, p210bcr-abl, and inhibited cell growth. This anti-bcr-abl ribozyme may be a useful tool to study the cell biology of Ph1+ leukemia and may ultimately have therapeutic potential in treating patients with Ph1 leukemias.

Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells

Blood ◽  
2014 ◽  
Vol 123 (25) ◽  
pp. 3932-3942 ◽  
Author(s):  
Fumio Nakahara ◽  
Jiro Kitaura ◽  
Tomoyuki Uchida ◽  
Chiemi Nishida ◽  
Katsuhiro Togami ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Key Points

Key Points Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1. MMP-9 is upregulated by Hes1, and MMP-9 deficiency impaired the development of CML-BC–like disease induced by BCR-ABL and Hes1 in mouse BMT.

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