scholarly journals Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2989-2995 ◽  
Author(s):  
L Stenke ◽  
C Edenius ◽  
J Samuelsson ◽  
JA Lindgren
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
High Performance ◽  
Uv Spectroscopy ◽  
Chronic Phase ◽  
Myeloproliferative Disorders ◽  
Myelogenous Leukemia ◽  
Platelet Dysfunction ◽  
Blastic Crisis ◽  
Leukotriene A4 ◽  
12 Lipoxygenase

Abstract The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.

scholarly journals Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2989-2995 ◽  
Author(s):  
L Stenke ◽  
C Edenius ◽  
J Samuelsson ◽  
JA Lindgren
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
High Performance ◽  
Uv Spectroscopy ◽  
Chronic Phase ◽  
Myeloproliferative Disorders ◽  
Myelogenous Leukemia ◽  
Platelet Dysfunction ◽  
Blastic Crisis ◽  
Leukotriene A4 ◽  
12 Lipoxygenase

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.

scholarly journals Association of the translocation (15;17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blastic crisis

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 270-274 ◽  
Author(s):  
S Misawa ◽  
E Lee ◽  
CA Schiffer ◽  
Z Liu ◽  
JR Testa
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Crisis ◽  
Cytogenetic Studies ◽  
Chromosomal Breakpoints ◽  
Variant Translocation ◽  
Marrow Cells

Abstract Cytogenetic studies were performed on nine patients with acute promyelocytic leukemia. Every patient had an identical translocation (15;17) or, in one case, a variant three-way rearrangement between chromosomes 7, 15, and 17. Another patient with chronic myelogenous leukemia was examined at the time of blastic crisis when the patient's bone marrow was infiltrated by hypergranular promyelocytes and blasts. Bone marrow cells contained a t(15;17) as well as a Ph1 chromosome. Only the latter abnormality was observed in the chronic phase of the disease. The translocation (15;17) was detected in all ten patients when bone marrow or peripheral blood cells were cultured for 24 hours prior to making chromosome preparations. However, the t(15;17) was not seen in three of these same cases when bone marrow cells were processed directly. These findings indicate that the t(15;17) is closely associated with acute proliferation of leukemic promyelocytes and that detection of this karyotypic defect may be influenced by the particular cytogenetic processing method used in different laboratories. An analysis of the banding pattern in the variant translocation provided additional evidence favoring chromosomal breakpoints at or very near the junction between bands 17q12 and 17q21 and at 15q22.

Correlation of the Site of M-bcr Breakpoint with Chronic Phase Duration, Blastic Crisis Lineage and Thrombocytosis in Ph1-Positive Chronic Myelogenous Leukemia

1995 ◽  
Vol 18 (3-4) ◽  
pp. 335-339 ◽  
Author(s):  
Nora-Athina Viniou ◽  
Marina Matzourani ◽  
Xenophon Yataganas ◽  
John Meletis ◽  
Gerassimosha Pangalis ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Crisis ◽  
Phase Duration

scholarly journals Selective sensitivity of chronic myelogenous leukemia cell populations to alkyl-lysophospholipids

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 519-523
Author(s):  
R Andreesen ◽  
M Modolell ◽  
PG Munder
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Leukemia Cell ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Crisis ◽  
Blood Leukocytes ◽  
Chronic Myelogenous Leukemia Cell ◽  
Cleavage Enzyme ◽  
Maturation Stages ◽  
Selective Sensitivity

In order to evaluate the specificity of alkyl-lysophospholipid-induced cell destruction, peripheral blood leukocytes from chronic myelogenous leukemia (CML) patients in chronic phase of the disease as well as in blastic crisis have been separated by density centrifugation. These subpopulations, enriched for the different maturation stages, were tested for their sensitivity to alkyl-lysophospholipids. It is shown that myelocytes in chronic phase CML are resistant, but blast cells from both clinical stages as well as maturational defective myelocytes from blastic crisis CML are highly sensitive to these antimetabolites. In contrast to chronic phase CML myelocytes, these sensitive cells show a high lysophospholipid adsorption rate and lack an O-alkyl-cleavage enzyme.

scholarly journals Selective sensitivity of chronic myelogenous leukemia cell populations to alkyl-lysophospholipids

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 519-523 ◽  
Author(s):  
R Andreesen ◽  
M Modolell ◽  
PG Munder
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Leukemia Cell ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Crisis ◽  
Blood Leukocytes ◽  
Chronic Myelogenous Leukemia Cell ◽  
Cleavage Enzyme ◽  
Maturation Stages ◽  
Selective Sensitivity

Abstract In order to evaluate the specificity of alkyl-lysophospholipid-induced cell destruction, peripheral blood leukocytes from chronic myelogenous leukemia (CML) patients in chronic phase of the disease as well as in blastic crisis have been separated by density centrifugation. These subpopulations, enriched for the different maturation stages, were tested for their sensitivity to alkyl-lysophospholipids. It is shown that myelocytes in chronic phase CML are resistant, but blast cells from both clinical stages as well as maturational defective myelocytes from blastic crisis CML are highly sensitive to these antimetabolites. In contrast to chronic phase CML myelocytes, these sensitive cells show a high lysophospholipid adsorption rate and lack an O-alkyl-cleavage enzyme.

scholarly journals Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 485-490 ◽  
Author(s):  
M Shtalrid ◽  
M Talpaz ◽  
R Kurzrock ◽  
H Kantarjian ◽  
J Trujillo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Chronic Myelogenous Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Blastic Crisis ◽  
Phase Duration ◽  
Dna Fragment

Abstract Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3′ bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

scholarly journals Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 485-490
Author(s):  
M Shtalrid ◽  
M Talpaz ◽  
R Kurzrock ◽  
H Kantarjian ◽  
J Trujillo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Chronic Myelogenous Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Blastic Crisis ◽  
Phase Duration ◽  
Dna Fragment

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3′ bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

scholarly journals Association of the translocation (15;17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blastic crisis

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 270-274 ◽  
Author(s):  
S Misawa ◽  
E Lee ◽  
CA Schiffer ◽  
Z Liu ◽  
JR Testa
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Crisis ◽  
Cytogenetic Studies ◽  
Chromosomal Breakpoints ◽  
Variant Translocation ◽  
Marrow Cells

Cytogenetic studies were performed on nine patients with acute promyelocytic leukemia. Every patient had an identical translocation (15;17) or, in one case, a variant three-way rearrangement between chromosomes 7, 15, and 17. Another patient with chronic myelogenous leukemia was examined at the time of blastic crisis when the patient's bone marrow was infiltrated by hypergranular promyelocytes and blasts. Bone marrow cells contained a t(15;17) as well as a Ph1 chromosome. Only the latter abnormality was observed in the chronic phase of the disease. The translocation (15;17) was detected in all ten patients when bone marrow or peripheral blood cells were cultured for 24 hours prior to making chromosome preparations. However, the t(15;17) was not seen in three of these same cases when bone marrow cells were processed directly. These findings indicate that the t(15;17) is closely associated with acute proliferation of leukemic promyelocytes and that detection of this karyotypic defect may be influenced by the particular cytogenetic processing method used in different laboratories. An analysis of the banding pattern in the variant translocation provided additional evidence favoring chromosomal breakpoints at or very near the junction between bands 17q12 and 17q21 and at 15q22.

scholarly journals Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3142-3147 ◽  
Author(s):  
M Wetzler ◽  
R Kurzrock ◽  
Z Estrov ◽  
H Kantarjian ◽  
H Gisslinger ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Interleukin 1 ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Interleukin 1 Beta ◽  
Blastic Crisis ◽  
The Mean ◽  
Lower Limits

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 1052-1057
Author(s):  
T Motoi ◽  
T Uchiyama ◽  
T Hori ◽  
K Itoh ◽  
H Uchino ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Blastic Crisis ◽  
Phase Range

We examined the expression of cell-surface interleukin-2 (IL-2) receptor (Tac antigen) on peripheral blood leukemic cells and measured soluble IL-2 receptor p55(alpha) chain (sIL-2R) levels in sera from chronic myelogenous leukemia (CML) patients with blastic crisis. Flow cytofluorometric analysis performed by dual immunofluorescence in three cases demonstrated coexpression of Tac antigen with myeloid (CD13, CD14, or CD33) or lymphoid (CD10) antigen on significant proportions of peripheral blood leukemic cells. Radiolabeled IL-2-binding assay demonstrated the specific IL-2 binding sites in three cases examined. The exogenous IL-2, however, failed to induce proliferative response. A myeloid cell line, Yut-K3, established from peripheral blood leukemic cells from a CML patient with blastic crisis, also expressed cell- surface Tac antigen and CD13 concurrently. SIL-2R assay showed that Yut- K3 released a detectable amount of sIL-2R in its culture supernatant. The serum sIL-2R levels were significantly elevated (range: 2,580 to 172,000 U/mL) in 12 CML patients with blastic crisis and were slightly elevated in ten patients in chronic phase (range: 250 to 820 U/mL) and in three in accelerated phase (range: 790 to 1,305 U/mL) compared with those in 24 normal controls (range: 70 to 695 U/mL, P less than .01). These results indicated that the leukemic cells from CML patients with blastic crisis expressed and released IL-2 receptor (Tac antigen). Longitudinal studies performed in three cases of CML with blastic crisis showed that the change of serum sIL-2R level was closely associated with that of the number of peripheral blood leukocytes and blasts, the percentage of blasts and serum LDH levels, also suggesting that the serum sIL-2R level is a useful clinical indicator of the leukemic cell burden in vivo.

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