ALBERT

Description: To characterize the prodromal phase of adult T-cell leukemia (ATL), a prospective follow-up study was conducted on 50 carriers in a putative pre-ATL state. This state was defined by the presence of molecularly- detectable monoclonal proliferation of human T-lymphotropic virus type I (HTLV-I)-infected T lymphocytes, and the absence of clinical symptoms of leukemia. The median observation time was 50 months. The pre-ATL subjects were divided into two groups according to initial white blood cell (WBC) counts: group A, those with a normal WBC count (9,000/microL) (n = 30), and group B, those with an increased WBC count (9,000 to 15,000) (n = 20). Comparisons were made between the two groups and with a group of 25 patients with chronic ATL (group C) who had WBC counts of more than 15,000. Significant differences in survival rate were found between groups A and B (10-year survival 65.7%) and group C (32.8%) (P 〈 .01), and between group A (10-year survival 90.0%) and group B (52.1%) (P 〈 .05). The incidence of transformation to overt ATL was 10% (3 of 30) in group A and 50% (10 of 20) in group B (P 〈 .01). In six transformed cases (one in A and five in B) we found exactly the same integration sites in pre-ATL and overt ATL phases, confirming the multistep leukemogenesis hypothesized for this disease. However, the pre-ATL subjects could be divided into two distinct prognostic groups based on the initial WBC count; those with good and those with poor prognosis. Although the 10% transformation rate (2.5% annually) in group A seemed to be extremely high compared with that in the general population of HTLV-I carriers (around 0.06% to 0.4% annually), the majority of group A subjects and some in group B showed stable clinical courses without transformation. Further, development of ATL was not observed in four group A subjects with HTLV-I-associated myelopathy (HAM), which is rarely associated with ATL. We propose to call this group of rather benign HTLV-I carriers “HTLV-I carriers with monoclonal proliferation of T lymphocytes (HCMPT).” Thus far we have been unable to identify reliable parameters other than WBC counts that prospectively distinguish HCMPT from the true pre-ATL state, in which there is a high probability of developing ATL. Further clinical and biologic approaches should elucidate the natural history of the HTLV-I carrier state and early events in ATL leukemogenesis.

Description: Most data suggest that malignant transformation in chronic myelogenous leukemia (CML) occurs in hematopoietic stem cell that is the progenitor of myelopoiesis and of B but not T lymphopoiesis. We established a T- lymphoid cell line (CML-T1) from a person with Ph-chromosome-negative CML in acute phase. Evidence of its T-lymphocyte origin includes the pattern cytochemical reactivity, reactivity with anti-T-cell monoclonal antibodies (MoAbs), and rearrangement of the beta-T-cell receptor (TCRB) gene. CML-T1 cells have features of type IV thymocytes. Cytogenetic analyses indicate a 47,XX, del(11), t(6;7)(q23;q24), +mar karyotype. CML-T1 cells exhibit molecular changes typical of CML, including translocation of the ABL protooncogene from chromosome 9 to 22, rearrangement of the BCR gene, and transcription of a chimeric BCR- ABL messenger RNA (mRNA). The ABL insertion on chromosome 22 appears interstitial, similar to other cases of Ph-chromosome-negative CML. These data clearly indicate that T cells can be involved in acute-phase CML. CML-T1 should be useful in studying this process as well as that underlying Ph-chromosome-negative CML.

Description: We report the clinical, hematologic, and immunologic features of 18 preleukemic adult T cell leukemia (pre-ATL) cases with abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus (HTLV/ATLV). The patients were from the Nagasaki district, which is one of the most endemic areas of ATL in Japan. Pre-ATL is a subclinical T cell abnormality differing from ATL. It is characterized by an insidious onset and appearance of abnormal T lymphocytes (10% to 40%) in the peripheral blood without clinical symptoms except for a few cases transiently presenting fever, skin eruptions, and slight lymphadenopathies. Most abnormal T lymphocytes were small and mature with incised or lobulated nuclei and formed E rosettes with sheep RBCs. Virologic and biomolecular analysis revealed that all cases were infected with HTLV, and proviral DNA was integrated in host lymphocytes from 12 of the 14 cases examined. Furthermore, the lymphocyte populations, including abnormal T lymphocytes, were monoclonal with respect to the site of the provirus integration. Abnormal T lymphocytosis persisted from one to more than seven years in six cases, three of which developed ATL after a one- to five-year pre-ATL stage, whereas abnormal T lymphocytes spontaneously decreased in the other seven patients. However, HTLV-infected monoclonal lymphocytes were detected in four cases examined, even after most of the abnormal T lymphocytes had disappeared. Moreover, the same clonally provirus- integrated lymphocytes persisted in two of four cases not only during the course of abnormal lymphocytosis, but also in the subsequent almost- normal blood. These results indicate that the majority of the cases were in a pre-ATL state with a potential to develop ATL.

Description: Surface phenotypes of leukemic cells from six patients with adult T cell leukemia (ATL) were analyzed by the use of monoclonal antibodies, both at the time of initial diagnosis and at either relapse or exacerbation phase after chemotherapy. Changes of cell surface antigens were observed in four of the six cases. The majority of the leukemic cells of these patients were reactive with anti-Leu-1 and anti-Leu-3a, but unreactive with anti-Leu-2a and MAS 036c monoclonal antibodies at the time of initial diagnosis, indicating that ATL cells are of peripheral inducer/helper T cell origin. In three cases, the Leu-1 antigen disappeared at relapse or at exacerbation phase, and in one of these cases, a small percentage of ATL cells became reactive with MAS 036c, which identifies cortical thymocyte antigen. ATL cells of one other case did not have Leu-1 antigen from the start, but gained Leu-2a antigen at exacerbation phase and became double-labeled cells (Leu-2a+, 3a+), which is known to be a feature of thymocytes. Thus, it appeared that ATL cells sometimes change their surface phenotype to that of an earlier stage of T cell differentiation at relapse or at exacerbation phase. Chronic myelocytic leukemia (CML) cells also usually change to immature cells at blastic crisis involving morphological change. However, this morphological change was not so prominent in the ATL cases studied, except one, in which typical ATL cells with nuclear indentation changed to large immature cells with basophilic cytoplasm at relapse.

Description: Surface phenotypes of leukemic cells from six patients with adult T cell leukemia (ATL) were analyzed by the use of monoclonal antibodies, both at the time of initial diagnosis and at either relapse or exacerbation phase after chemotherapy. Changes of cell surface antigens were observed in four of the six cases. The majority of the leukemic cells of these patients were reactive with anti-Leu-1 and anti-Leu-3a, but unreactive with anti-Leu-2a and MAS 036c monoclonal antibodies at the time of initial diagnosis, indicating that ATL cells are of peripheral inducer/helper T cell origin. In three cases, the Leu-1 antigen disappeared at relapse or at exacerbation phase, and in one of these cases, a small percentage of ATL cells became reactive with MAS 036c, which identifies cortical thymocyte antigen. ATL cells of one other case did not have Leu-1 antigen from the start, but gained Leu-2a antigen at exacerbation phase and became double-labeled cells (Leu-2a+, 3a+), which is known to be a feature of thymocytes. Thus, it appeared that ATL cells sometimes change their surface phenotype to that of an earlier stage of T cell differentiation at relapse or at exacerbation phase. Chronic myelocytic leukemia (CML) cells also usually change to immature cells at blastic crisis involving morphological change. However, this morphological change was not so prominent in the ATL cases studied, except one, in which typical ATL cells with nuclear indentation changed to large immature cells with basophilic cytoplasm at relapse.

Description: A semiquantitative estimation of human T-lymphotropic virus type I (HTLV-I) integration by peripheral blood mononuclear cells (PBMC) was performed. Genomic DNA samples derived from 134 HTLV-I carriers were subjected to 40 or 60 cycles of the polymerase chain reaction to amplify the pol region of HTLV-I. The HTLV-I genome was detected by dot hybridization using a 32P-labeled oligonucleotide probe for the pol region. The radioactivity of hybridized dot membranes was then counted with an RI Imaging System (Ambis Inc, San Diego, CA) and the HTLV-I genome dose was determined by comparison with standard curve for serially diluted HTLV-I genome-positive DNA. A wide range of variation of HTLV-I genome integration was observed. When the integrated genome dose was calculated as the number of HTLV-I copies per 100 PBMC, 7 carriers (5%) had more than 10 copies, 56 (42%) had 1 to 10 copies, 46 (34%) had 0.1 to 1 copy, and 24 (18%) had less than 0.1 copy. In one sample, the HTLV-I genome was undetectable, which may indicate that the integrated genome was present at less than 0.01 copies per 100 PBMC. Age- or sex-related variations in the distribution of individuals with different HTLV-I genome were rather limited. However, carriers with a high level of the HTLV-I genome were always more than 30 years old and were predominantly male (six of seven).