Longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia using archived blood smears.

We performed a longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia and a follow-up of at least 2.5 years after diagnosis. Point mutations at codons 12, 13, and 61 of the N-ras oncogene were analyzed after in vitro amplification of N-ras specific sequences followed by dot-blot hybridization. Lysed cells scraped from archived blood and bone marrow smears were used as template for a polymerase chain reaction. In 3 of 90 patients tested (3.3%), a mutation in codon 12 could be detected in the most recent blood smears. All available blood and bone marrow samples of these patients were subsequently analyzed for the occurrence of that particular mutation. In all three cases the mutation was not detectable at diagnosis, but was acquired later during the course of the disease. In two of these patients this event was associated with rapid deterioration and transformation to acute leukemia. However, the third patient showed a protracted course during a period of 5 years after acquisition of the mutation. These results indicate that activation of the N-ras protooncogene in these three patients represents a secondary phenomenon associated with disease progression in some cases, but compatible with stable disease in others.

der(1)t(1;9): a specific chromosome abnormality in polycythemia vera? Cytogenetic and in situ hybridization studies.

Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one patient this was found as the sole abnormality. The other patient originally presented with trisomy 9 but later developed an extra der(1) during the further course of the disease with disapperance of the extra chromosome 9. In situ hybridization studies on this latter patient proved that the centromere of chromosome 1 was involved in the formation of the derivative chromosome.

Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases.

The utility and prognostic significance of the FAB classification was studied in 237 patients with a myelodysplastic syndrome. No significant differences in actuarial survival and probability of transformation to acute leukaemia were found in patients with RA, AISA or CMML. The median survival time for the RA group was 50 months, for the AISA and CMML subclasses more than 60 months. The probability of transformation for the RA, AISA and CMML subgroups showed a linear trend with a probability of 25% for the RA, 16% for the AISA and of 18% for the CMML groups after a 5 year observation period. A uniformly poor prognosis was found for the RAEB and RAEB/t subgroups with median survival times of respectively 9 and 6 months. Chromosomal abnormalities were found in 68 out of 155 patients (44%). Patients with only normal metaphases or with abnormal metaphases together with karyotypic normal cells had a longer median survival time and a lower probability for transformation as compared to those with only abnormal metaphases. The most important factor in prognosis is the number of blast cells in blood and bone marrow. Age and sex, and certain quantitative and qualitative abnormalities in the peripheral blood appear of limited prognostic value for patients with RA, AISA and CMML. The longer life expectancy of 35 patients with CMML as compared to other series seems to be related to the percentage of blast cells at the time of diagnosis.

Trisomy of chromosome 22 in acute myelomonocytic leukemia.

A patient with acute myelomonocytic leukemia type M4, with a trisomy 22 as the only chromosomal abnormality is reported. All six previously published cases with this anomaly had acute myeloid leukemia. The subtype was AMMoL in five patients, and the subtype of the sixth one was not indicated.

Translocation 1;7 in hematologic disorders: a brief review of 22 cases.

A translocation t(1;7)(p11;p11), previously reported in patients with myelodysplasia or leukemia has been found in seven new cases. The present report briefly reviews the cytogenetic and clinical features of 22 patients with this translocation. The majority of these patients had a history of occupational or therapeutic exposure to toxic substances or radiation. Trisomy 8 or 21 were the most common additional abnormalities, especially in leukemic patients. The t(1;7) should be added to the group of specific cytogenetic abnormalities observed frequently in secondary myelodysplasia and leukemia.

Malignant hematologic disorders in two Robertsonian 13;14 translocation carriers.

Two patients with a malignant hematologic disorder appeared to carry a constitutional Robertsonian 13;14 translocation. The presence of this translocation in relation to hematologic diseases is discussed. No conclusion can be made at present on the observed association. The translocation might predispose to malignant transformation, but its presence might also be purely coincidental.

Chronic myeloid leukemia in myasthenia gravis after long-term treatment with 6-mercaptopurine.

A woman with myasthenia gravis and a thymoma did not respond sufficiently to thymectomy. She was treated with 6-mercaptopurine. Withdrawal of this treatment was several times followed by an aggravation of myasthenic symptoms. After more than 12 1/2 years treatment she developed Ph1-positive chronic myeloid leukemia (CML). No other case of CML following immunosuppressive treatment has been described. Because the therapeutic agent is potentially leukemogenic, the possibility cannot be definitely excluded that the development of CML is not a mere coincidence.

The preleukemic syndrome. II. Cytogenetic findings.

Out of 151 patients with preleukemic syndrome, bone marrow chromosome studies were carried out in 88 during the preleukemic phase and in 10 after blastic transformation. Out of 54 cases studied without banding techniques, 13 (24%) were abnormal, while 17 (50%) out of 34 banded cases showed abnormalities. This highly significant increase in yield of aberrations was not restricted to structural abnormalities. During the preleukemic phase of the disease, only 5 of the abnormal patients had no normal metaphases in their bone marrow. Four types of chromosome aberrations were observed more than once: -Y, +8, del 5q and del F or del 20q. They are all frequently observed in myeloproliferative disorders. After blastic transformation, 15 out of 19 patients were abnormal and the abnormalities were more complex. It seems, therefore, that a qualitative and quantitative difference exists between this group of patients and the published series of patients with ANLL. Small abnormal cell lines with the same chromosome abnormalities as in the bone marrow were observed in PHA-stimulated blood cultures of 9 patients. Unstimulated cultures of the same blood sample did not show any mitosis. It is suggested that small subpopulations of lymphocytes arose from the same pluripotent stem cell as the leukemic myelogenous cells, although there may be other explanations.

The preleukemic syndrome. I. Clinical and hematological findings.

A long-term prospective study including 151 patients with preleukemia was performed in 1958--79. The series comprised 78 women and 73 men with a mean age of 79 and 72 years, respectively. Acute leukemia was the cause of death in 35 patients, 61 died of infections and/or hemorrhage or of unrelated causes. The mean interval between the initial diagnosis and death from acute non-lymphocytic leukemia was 36 months (range 2--121). Pitfalls in diagnosis are extensively discussed. The most striking was the advanced age of the patients. The presence of pancytopenia at the time of diagnosis was not predictive for subsequent blastic transformation.