Ph1-positive Cases Research Articles

Chronic granulocytic leukemia: Reassessment of morphologic and cytogenetic characteristics in Ph1-positive and Ph1-negative cases

33 cases of chronic granulocytic leukemia (CGL) were reassessed to determine if, by strict morphologic criteria. Philadelphia chromosome (Ph1)-negative CGL exists as a diagnostic entity and if Ph1-positive CGL could be distinguished from Ph1-negative CGL. Cases were reassessed using published criteria and, of 11 Ph1-negative cases, only 4 could be reclassified as myelodysplastic syndromes or undifferentiated chronic myeloproliferative disorder. Of the morphologic parameters evaluated, peripheral blood basophilia and bicytopenia proved to be good discriminators between Ph1-positive and Ph1-negative cases. As a group, Ph1-negative cases were more heterogeneous and tended to have lower hemoglobin, WBC, platelet count and absolute eosinophilia. Chromosomal abnormalities other than Ph1 were seen only in the Ph1-positive cases. Based on these findings, we conclude that Ph1-negative CGL constitutes a heterogeneous group, a subgroup of which is morphologically identical with the Ph1-positive CGL. The parameters that best discriminate between Ph1-positive and Ph1-negative cases are peripheral blood absolute basophilia and bicytopenia.

Possible Autocrine Mechanism of Placenta Growth Factor / Vascular Endothelial Growth Factor Receptor Type 1 in Acute Lymphoblastic Leukemia with Philadelphia Chromosome.

The growth and/or survival of leukemia cells are affected by endothelial cell associated factors such as vascular endothelial growth factor (VEGF). Here, we studied the mRNA expression of VEGF and placenta growth factor (PLGF), a VEGF-related molecule, of acute lymphoblastic leukemia (ALL) cells (10 Philadelphia chromosome (Ph1) positive cases and 10 Ph1 negative cases) by real-time PCR. The expression of PLGF mRNA was significantly higher in Ph1 positive cases than Ph1 negative cases (p<0.05). The expression of VEGF mRNA was not different between Ph1 positive and negative cases. Then, recombinant PLGF was added to the culture of ALL cell lines: the growth of CRL1929 (Ph1 positive) was augmented by PLGF in a dose-dependent manner, while the growth of Nalm6 (Ph1 negative) was not affected by the addition of PLGF. Here, the growth enhancement effect of PLGF on CRL1929 was cancelled by the simultaneous addition of VEGF receptor type 1-Fc (VEGFR1-Fc), which binds to PLGF and abrogates the function. The growth enhancement effect was not cancelled by the simultaneous addition of VEGFR2-Fc, which binds to VEGF, but not to PLGF. Recombinant VEGF did not affect the growth of either cell line. Our data demonstrated that PLGF has a growth promoting effect on Ph1 positive ALL cells, and autocrine mechanism of PLGF-VEGFR1 might work in Ph1 positive ALL.

Cytogenetics of chronic myelogenous leukemia (CML) correlated to the histopathology of bone marrow biopsies

Cytogenetic findings were correlated to histopathological bone marrow findings evaluated simultaneously in 103 patients with chronic myelogenous leukemia (CML). CML was subtyped histologically according to the number of megakaryocytes and increase of fibers or blasts within the bone marrow. The Philadelphia chromosome (Ph 1) was found in 88.3% of all patients (91/103). Chromosome aberrations additional to the Ph 1-chromosome were noticed in 20 of 91 (22%) cases. The additional karyotype changes occurred significantly more frequently among patients with increase of fibers in the bone marrow compared with patients without increase of fibers or blasts (p less than 0.05). Karyotype changes associated with increase of fibers in Ph 1-positive cases of CML were trisomy 8 and 19, +Ph1, t (1; 11), and i (17q). Ph 1-positive CML patients with additional karyotype changes had a significantly shorter survival (p less than 0.04) than Ph 1-positive patients without additional chromosome aberrations. Our results suggest that histopathological examination of the bone marrow should be considered in the evaluation of cytogenetic markers in chronic myeloproliferative disorders.

The incidence, type, and subsequent evolution of 14 variant Ph 1 translocations in 180 South African patients with Ph 1-positive chronic myeloid leukemia

A Philadelphia (Ph 1) chromosome translocation was found in 180 of 198 cases of chronic myeloid leukemia (CML). A standard t(9;22) was present in 166 patients, 83 of whom were black, 79 white, and 4 of “mixed” ancestry; whereas a variant Ph 1 translocation was detected in 14 patients (7.8%), 11 of whom were black and only 3 white. There was a higher frequency of a variant Ph 1 among black patients compared with whites. The significantly higher frequency of a variant among our patients compared with surveys from elsewhere could be due to differing environmental agents. Simple variants were detected in four patients. Complex variants were found in eight cases; in one of these patients, only chromosomes #9 and #22 were involved, but a complex rearrangement of chromosome #9 had occurred. A “masked” Ph 1 translocation was detected in two cases, both of which showed monosomy #22 because the Ph 1 chromosome was incorporated or interchanged with chromosome #9. Karyotypic evolution of the Ph 1-positive cell line was observed more frequently in the variant group (71.4%) than the standard group (29.5%). This difference was significant (p < 0.005). There was no difference in the type of clonal changes seen in standard and variant groups. The majority of clonal changes were observed during the acute stage in both groups. In the variant group, there was no obvious correlation between the type of variant, type of clonal change, blast morphology, or survival. Their initial survival pattern resembled that of Ph 1-negative cases, but those patients who survived longer than 1 year showed a survival trend similar to standard Ph 1-positive cases. Possible explanations for the specificity of chromosome #22 involvement and the constancy of the 22q11 breakpoint in all these variant translocations are discussed.

Chromosomes and causation of human cancer and leukemia.XXIX.Further studies on karyotypic progression in CML

Fifty-seven Ph1-positive cases of chronic myelocytic leukemia (CML) were analyzed with chromosomal banding techniques and their karyotypic progression followed. These cases included 1 without evidence of a Ph1-translocation and 1 new patient with a complex Ph1-translocation involving chromosomes No. 9, No. 17 and No. 22. Of the 57 patients, 28 had the Ph1 as the only karyotypic anomaly, whereas the remaining 29 cases developed and/or were associated with chromosomal changes usually of a hyperdiploid nature, particularly in the blastic phase, in addition to the Ph1. Even though the additional karyotypic changes frequently included chromosomes No. 8, No. 17, No. 19 and No. 21, a large number of others was also involved, although less often. The series included 3 cases with different types of translocations unrelated to the Ph1. The cytogenetic observations have been correlated with some of the clinical parameters. The survival of the patients was evaluated in relation to the karyotypic findings, indicating that the chromosomal changes may not play as important a role in the prognostic and progressive aspects of Ph1-positive CML as that of other as yet undetermined factors.

Chromosomes and causation of human cancer and leukemia. XVI. Banding studies of chronic myelocytic leukemia, including five unusual Ph11 translocations.

Forty-two Ph1-positive cases of chronic myelocytic leukemia (CML) were examined with chromosomal banding techniques. Thirty-seven of these cases had the "standard" type of Ph1 translocation between chromosomes No. 9 and No. 22 [t(9;22)(q34;q11)] in the Ph1-positive marrow cells; 5 cases had unusual types of Ph1 translocation. Of the 37 cases, 21 had additional numerical and/or structural chromosomal changes, 2 had a missing Y chromosome, and 1 had an extra Ph1 in the Ph1-positive cells. In the 5 cases with unusual types of Ph1 translocation, chromosomes No. 2, No. 9 No. 10, and No. 13 were involved. The clinical picture in these 5 patients did not differ materially from that of the other Ph1-positive patients with CML, probably indicating that the recipient chromosome, with which the translocation from No. 22 takes place, does not play a crucial role in the course of the CML. In the 21 cases with abnormal karyotypes, nonrandom chromosomal changes were observed. Most of the changes were related to events occurring at the centromeric region. The prognosis of cases with only an extra No. 8 or Ph1 appears to be better than that for cases with an iso-17q [I(17a)] chromosome or other extra chromosomes. The presence of the Ph1 (delected No. 22) in every case points to the essentiality of this karyotypic findings in the diagnosis of CML and possibly in the genesis of the disease.