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We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.

Background. The authors conducted a survey of a large cohort of patients with adult T‐cell leukemia (ATL) and a group of human T‐cell leukemia virus type 1 (HTLV‐1) carriers to elucidate whether measurements of soluble interleukin‐2 receptor (sIL‐2R) levels are indicative of ATL tumor burden and correlate with clinical progression. Methods. Using a sandwich enzyme immunoassay, the authors determined sIL‐2R in the serum of 135 patients with ATL diagnosed and subclassified according to the Japan Lymphoma Study Group criteria and in the serum of healthy HTLV‐1 seropositive persons. Also included were patients in the preleukemic state of ATL (pre‐ATL), which is characterized by only slight blood changes but does not fit the diagnostic criteria of ATL. In the five subjects who finally advanced to overt ATL, the authors prospectively performed serial measurements of the receptor. Results. Serial measurements of sIL‐2R levels taken until overt ATL developed showed that these levels in the initial samples were higher than those of control subjects, even when subjects were asymptomatic or in the pre‐ATL state. The serial levels of the five subjects gradually increased despite being in a clinically stable condition, finally reaching markedly high levels at the time ATL became overt. The mean sIL‐2R levels of the smoldering, chronic, acute, and lymphoma subtypes of ATL were 1680 U/ml, 6680 U/ml, 45,940 U/ml, and 34,620 U/ml, respectively (P > 0.01). The sIL‐2R levels of each subtype at the time of diagnosis were more correlated with tumor burden, malignant behavior, and prognosis than lactate dehydrogenase (LDH) levels. In the low, moderate, and high sIL‐2R subgroups, the median survival time and percent survival probability at 2 years was 30.2 months (46.0%), 16.5 months (25.0%), and 7.7 months (15.3%), respectively. Conclusions. Serial measurements of sIL‐2R levels are of clinical importance because changes of the levels correlate with disease progression, especially in early phase of ATL. The data suggest that sIL‐2R may be more useful than LDH. In addition, emphasis may be placed on sIL‐2R as an indicator of ATL progression status and prognosis for survival. The value of this marker in clinical practice should be confirmed prospectively. Cancer 1994; 73:2753–8.

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We have established an erythropoietin-dependent human leuonly human leukemic cell line that is exclusively EPO depenkemia cell line, AS-E2, from a patient with acute myeloid leukedent. Because of its late erythroid cell characteristics and its mia. These cells have many characteristics of late erythroid strict EPO dependency, we think that AS-E2 is a good model progenitor cells, they are positive for CD36, Glycophorin A, and to study the effect of EPO on erythroid cell growth and signal (ASD-chE), but some of them were positive for periodic acidand they also play an integral role in leukemic cell growth. [6][7][8][9][10][11][12] and are useful tools for the cloning of cytokine therapy was initiated including bephenoyl Ara-c, daunorubicgenes, cytokine receptor genes, and for studying signal transine and 6MP. A complete remission was obtained in March, duction after cytokine stimulation and the role of cytokines in but the leukemia relapsed in May 1993. The leukemia became hematopoiesis. Among many cytokines, erythropoietin (EPO) resistant to chemotherapy and the patient died in September is an important cytokine which regulates commitment, 1993. growth, differentiation and/or survival of erythroid lineage cells through its interaction with a specific receptor, especially at the late stage of erythroid progenitors like BFU-E, CFU-E or Cell culture and cell count more mature erythroid cells. 13,14 Although some EPO-responsive human leukemia cell lines have been reported, most of AS-E2 cells were cultured in Iscove's modified Dulbecco's them also respond to other cytokines, such as granulocytemedium (IMDM) supplemented with 20% heat inactivated macrophage colony-stimulating factor (GM-CSF) or interleufetal bovine serum (FBS) in the presence of 2 U/ml of EPO kin-3 (IL-3). 8,9 and antibiotics. The data were generated after 12 months of In this paper, we report the establishment and the charactercontinuous culture. To examine EPO dependency, AS-E2 cells istics of a new human leukemia cell line, AS-E2, which shows were washed twice with IMDM and resuspended in IMDM some features of late erythroid lineage cells and exclusive EPO containing 20% FBS without EPO. AS-E2 cells were also culdependency in its growth. As far as we know, AS-E2 is the tured in the presence of both EPO and rabbit anti-human EPO antibody in order to inhibit the EPO effect in the culture medium.