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J Minowada

Publications and source records attributed to J Minowada.

At least 55 records · Page 3Linked to original sources

Isolation and amino acid sequence of a chemotactic protein, LECT/interleukin 8, from a human myeloid leukemia cell line, ML-1.

We looked for chemotaxin/interleukin 8 (CT/IL-8) activity in the culture fluids of 97 human leukemia cell lines and found it in two of the T cell lines, six of the myeloid cell lines, and one of the normal B-cell lines. It was particularly strong in the culture fluids of two cell lines. These cell lines secreted a chemotactic protein into the culture fluids under certain conditions of stimulation with phorbol-12-myristate 13-acetate (PMA), lipopolysaccharide, or hemagglutinin-P. A myeloid leukemia cell line, ML-1, secreted an inducible chemotaxin when stimulated with PMA (1 ng/ml) for 24 h. We purified the chemotaxin from ML-1 cell culture fluid using an improved procedure: concentration with DEAE-Sepharose CL-6B and CM-Sepharose CL-6B, CM-Sepharose column chromatography, and reverse-phase 5TMS-300 column on HPLC with the retention time coinciding with that of LUCT/IL-8 [Suzuki et al., 1989, J. Exp. Med. 169, 1895]. The yield was 200 micrograms protein from 6 liters of the culture fluid. The N terminus of CT/IL-8 was AVLPR-SAKELRXQXIKTYSK- - -, the same as that of LUCT/IL-8, which is constitutively secreted from lung giant cell carcinoma LU65C cells. The optimal concentration in the chemotactic activity of CT/IL-8, equivalent to that of bacterial chemotactic peptide fMet-Leu-Phe (10 nM), was found to be 5 nM. The results show that this chemotaxin is identical to LUCT/IL-8.

Amino Acid Sequence↗

Production of interleukin-1 alpha and interleukin-2 by separate, phenotypically different leukaemia and human T cell lymphotropic virus-1-transformed T cell clones.

The relationship between interleukin-1 (IL-1) and interleukin-2 (IL-2) production and immunophenotype marker profiles was studied in a panel of 29 leukaemia and human T cell lymphotropic virus-1 (HTLV-1)-transformed T cell lines. Culture supernatants from six of the 29 T cell lines tested increased IL-2 production by the MOLT-16 cell line in a manner similar to that of rIL-1 alpha or rIL-1 beta. The enhancing activity in the cell culture supernatants was inhibited by antibody against IL-1 alpha. Anti-IL-1 beta antibody had no inhibitory effect. All the cell lines producing IL-1 alpha had characteristics of activated mature T cells. They were terminal deoxyribonucleotidyl transferase (TdT)-, CD4+, CD8-, HLA-DR+ and all were strongly positive for IL-2R alpha (Tac antigen) expression. However, none of the IL-1 alpha producing cell lines secreted detectable IL-2. A significant quantity of IL-2 was found, after stimulation with phytohaemagglutinin, in supernatants from nine of the 29 cell lines tested. The majority of IL-2 producing cell lines originated from less mature, non-activated T cells, as they were characterized by the expression of TdT, lack of HLA-DR antigens and > 50% had no detectable IL-2R alpha. The results thus show that separate, phenotypically different leukaemia and HTLV-1-transformed T cell clones produce IL-1 alpha and IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗

Abnormal proportion of gamma delta T cells in peripheral blood is frequently detected in patients with periodontal disease.

The proportions of gamma delta T cells in the peripheral blood of 8 early-onset periodontitis (EOP) patients, 8 later-onset periodontitis (LOP) patients, and of 17 healthy subjects (HS) were assessed by immunofluorescence assay using an anti-pan gamma delta T cell monoclonal antibody (TCR-delta 1) to study the population attributes of peripheral blood gamma delta T cells in patients with periodontal disease. The distribution of the proportions of gamma delta T cells in both EOP and LOP patients was found to be one and one half times broader than that in the HS; however, there was no significant difference in the proportion of gamma delta T cells between each group. An abnormally high proportion of peripheral blood gamma delta T cells in pan T cells (> 9.90%) was observed in 37.5% of both the EOP patients and the LOP patients. An abnormally low proportion (< 5.57%) was observed in 50% of the EOP patients and in 25% of the LOP patients. The higher occurrences of the high or low gamma delta T cell proportions were significant between EOP and HS, and between EOP+LOP and HS. There was no correlation between the proportion of gamma delta T cells and age or the clinical parameters of periodontal status. It was concluded that an abnormal proportion of gamma delta T cells is frequently detected in patients with periodontal disease. These findings are consistent with the proposed role of the gamma delta T cells for playing a unique role as a first line defense against infections at body surfaces.

Adolescent↗

Characterization of 17 human immunodeficiency virus-1 carrier cell lines with T cell, myelomonocyte, or megakaryocyte lineages.

Of 29 hematopoietic cell lines tested for susceptibility to human immunodeficiency virus (HIV)-1HTLV-IIIB infection, all CD4+ cell lines became infected. Continuous culturing of infected cell lines resulted in nine HIV-1 carrier cell lines, including, for the first time, an HIV-1 carrier megakaryoblastic cell line, MEG-01/HIV. The immunophenotypic profiles of a total of 17 HIV-1 carrier cell lines (nine newly and eight previously established cell lines) were compared with their respective parental noninfected cell lines. Except for total absence of CD4 expression, the expression of other antigens was variable among the 17 HIV-1 carrier cell lines. Persistent and consistent replication of infectious HIV-1 was detected in all of them in varying quantities. The great variability observed in both the altered marker expression, with respect to that of the noninfected parental cell lines, and in the quantities of persistently produced infectious HIV-1 was, nevertheless, specific to the individual cell lines. Furthermore, the present study demonstrates that there is no apparent correlation in the quantity of HIV-1 produced to either T cell, myelomonocytic cell, or megakaryocytic cell types. Instead, the results suggest that a particular interaction between HIV-1 and individual clonal cell lines may provide insight into the extremely complex immune dysregulation associated with the pathogenesis of acquired immune deficiency syndrome. Thus, the 17 HIV-1 carrier cell lines of diverse origin presented here provide valuable and unique models for further understanding acquired immune deficiency syndrome pathogenesis at the cellular and molecular levels.

Adolescent↗

Possible new genetic marker for human lymphoid leukemias as detected by ribosomal protein S14 cDNA.

Two polymorphic restriction fragments (bands) were detected in human lymphoid leukemias using restriction enzyme HindIII and a DNA probe coding for the human ribosomal protein S14 gene. Seventy-four leukemia samples of either fresh or cultured cells (54 lymphoid and 20 non-lymphoid) and 28 normal leukocyte samples as controls were examined. Southern blot analysis of their genomic DNA showed that, in addition to seven distinct and invariant bands, two new bands of 3.0 kb and 1.8 kb were detected in 19 of 20 cases (95%) of T-cell leukemias and in 20 of 34 cases (59%) of B-cell and B-precursor-cell leukemias tested. These two new bands were not detected, however, in any of the 20 cases of myeloid leukemias, nor in any of the 28 cases of normal control samples. A fragment of approximately 400 bp sequences can be enzymatically amplified from the 3.0 kb and 1.8 kb size-selected genomic DNA by polymerase chain reaction. A processed pseudogene seems to be involved, as judged by the size of the amplified product. These results suggest this could be a genetic marker for lymphoid leukemias and may provide new insight into the heterogeneity of the genetic changes taking place in human hematopoietic malignancies.

Adolescent↗

12-0-Tetradecanoylphorbol 13-acetate (TPA)-induced enzymatic change of human non-T, non-B lymphoid leukemia cell lines.

Culture of two lymphoid leukemia cell lines with 5 x 10(-9) to 10(-7) M 12-0-tetradecanoyl-phorbol 13-acetate (TPA) induced the significant increase in sialyltransferase, acid phosphatase and butyrate esterase activities, the decrease in poly(A) polymerase and terminal deoxynucleotidyl transferase (TdT) activities. B4-, J5-, TdT- or PNA-positive cells were decreased in TPA-treated cells, while B1-positive cells were increased. These results suggest enzymatic changes as an aspect of TPA-induced differentiation in lymphoid leukemia cell lines. These enzymatic activities may be useful markers for the differentiation of lymphoid leukemia cells.

Cell Differentiation↗

A novel cell growth-promoting factor identified in a B cell leukemia cell line, BALL-1.

A novel leukemia cell growth-promoting activity has been identified in the culture supernatant from a human B cell leukemia cell line, BALL-1. The supernatant from unstimulated cultures of the BALL-1 cells significantly promoted the growth of 16 out of 24 leukemia/lymphoma cell lines of different lineages (T, B and non-lymphoid) in a minimal concentration of fetal bovine serum (FBS), and of 5 out of 12 cases of fresh leukemia cells in FBS-free medium. The growth-promoting activity in the BALL-1 supernatant has been further characterized using FPLC chromatography, molecular weight (MW) sieve filtration and dialysis. The MW of the factor was less than 10 kDa. The growth-promoting activity was heat and acid stable and resistant to trypsin treatment. The factor isolated from the BALL-1 supernatant was distinct from known polypeptide growth factors with MW below 10 kDa, such as epidermal growth factor, transforming growth factor alpha, insulin-like growth factor I (IGF-I), IGF-II and insulin, as determined by specific antibodies and by cell growth-promoting tests. The factor in the BALL-1 supernatant did not promote the proliferation of normal human fresh peripheral blood lymphocytes or mouse fibroblast cell line, BALB/c3T3. In addition to the BALL-1 supernatant, a similar growth-promoting activity was found in the culture supernatants from 13 of 17 leukemia/lymphoma cell lines tested. The activity in these culture supernatants promoted the growth of leukemia/lymphoma cell lines in autocrine and/or paracrine fashions. These observations suggest that the low MW cell growth-promoting activity found in the BALL-1 culture supernatant is mediated by a novel factor which may well be responsible for the clonal expansion of particular leukemic clones.

Cell Division↗

Enhancement of interleukin-2 (IL-2) production by 6 different cytokines: heterogeneity among IL-2 producing T cell clones.

The production of interleukin-2 (IL-2) by phytohemagglutinin (PHA)-stimulated human leukemia T cell lines was significantly increased by 6 different cytokines. The most effective cytokines were interleukin-1 alpha (IL-1 alpha) and IL-1 beta; less effective were interferon-alpha (IFN-alpha), tumor necrosis factor-alpha (TNF-alpha), IFN-beta and TNF-beta. The combinations of two cytokines had synergistic or additive effects and increased IL-2 production to a greater extent than either cytokine alone. Other cytokines tested, such as IL-3, IL-4, IL-6, IL-7, IL-8 and IFN-gamma, had no effect on IL-2 production. However, a remarkable heterogeneity in sensitivity to the enhancing effects of the active cytokines was found among the IL-2-producing T cell lines studied. While IL-2 production in the most sensitive cell line, MOLT-16, was increased by all 6 active cytokines, other cell lines responded by increasing IL-2 production to stimulation with only some of the cytokines tested. The production of IL-2 in T cell line H9 was not enhanced by any of the cytokines used. These results show that several cytokines can increase IL-2 production by having a direct effect on the activated IL-2-producing T cells, but also that the outcome of the regulatory effects of individual cytokines depends considerably upon the individual IL-2-producing T cell clone.

Cytokines↗

Interleukin-2 production by human leukemia cell lines of pre-B cell origin.

Cells of 7 tested human leukemia cell lines of pre-B cell origin (as characterized by immunophenotyping and by the expression of cytoplasmic mu chains, but not by surface immunoglobulins) produced after stimulation with bacterial lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) a lymphokine activity which supported the growth of the interleukin-2 (IL-2)-dependent CTLL-2 cell line. Three pieces of evidence indicate that the secreted lymphokine was functionally and antigenically very similar, if not identical, to human IL-2: (1) The lymphokine supported the growth of murine IL-2-dependent CTLL-2 cells, which did not respond to human lymphokines other than IL-2, but it did not stimulate the growth of murine IL-3-dependent FDC-P2 cells, (2) the biological activity of the lymphokine was inhibited by monoclonal antibody (mAb) anti-human-IL-2, and (3) the proliferation of IL-2-dependent cells in the presence of the active material was completely inhibited by the inclusion of the anti-mouse-IL-2 receptor (IL-2R) mAb. Since leukemia cells of immature B-cell origin also synthesize IL-2R, the human pre-B cell leukemias could represent another type of hematological malignancy where the autocrine processes of IL-2 production and utilization are involved in the expansion of the disease.

Animals↗

Multiple and heterogeneous patterns of cytokine production in 18 leukemia and in vitro transformed mature T cell lines reflect the individuality of human leukemias.

The relationship between cytokine production patterns and immunophenotype marker profiles was studied in a panel of 18 T cell lines originating from various types of hematological malignancies and from human T cell lymphotropic virus-I (HTLV-I)-transformed cells. The production of 11 different cytokines by both unstimulated and phytohemagglutinin (PHA)-stimulated cells was tested. The production of interleukin-1 alpha (IL-1 alpha), IL-2, IL-3/granulocyte-macrophage colony stimulating factor (GM-CSF), IL-4, IL-5, IL-6, tumor necrosis factor-alpha (TNF-alpha), TNF-beta and interferon-gamma (IFN-gamma) by some of the cell lines was detected, and no cell line produced IL-1 beta or IFN-alpha. All 4 cell lines producing IL-1 alpha also produced other inflammatory cytokines, namely, IL-6, TNF-alpha and TNF-beta, but they did not produce IL-2. The IL-1 alpha-producing cell lines had the phenotype of mature, activated T cells, regardless of leukemia or transformant origin (TdT-, CD4+, CD8-, IL-2R+, HLA-DR+) and all were HTLV-1+. However, the production of other cytokines followed a random distribution, and no relationship emerged between cytokine production patterns and alpha/beta or gamma/delta type of T cell receptor (TcR) expression, immunophenotypic marker profiles, or the clinical origin of the cells. These results thus show that human leukemia and HTLV-I-transformed T cell lines can produce a large number of biologically active cytokines and that, except for the association of inflammatory cytokine production with mature activated cells, random patterns of cytokine production reflect the individuality of leukemia cell lines.

Cell Line, Transformed↗

Detection of bcl-2 protein and bcl-2 messenger RNA in normal and neoplastic lymphoid tissues by immunohistochemistry and in situ hybridization.

bcl-2 protein has been detected in surgical specimens and cultured permanent cell lines of non-Hodgkin's lymphomas and leukemias using enzyme immunohistochemistry and immunofluorescence with anti-bcl-2 monoclonal antibodies. Of 40 surgical specimens, bcl-2 protein was expressed in 50% of B-cell and 41% of T-cell lymphomas, both with and without the bcl-2 gene rearrangement. In investigations of 38 hematopoietic cell lines, bcl-2 protein was detected not only in lymphoid cell lines but also in myeloid cell lines. In situ hybridization and immunohistochemical analysis of reactive lymph nodes showed that lymphocytes in mantle zones and paracortical areas expressed bcl-2 protein consistent with the messenger RNA distribution and that germinal center cells showed abundant bcl-2 transcript, despite the absence of detectable bcl-2 protein. These results suggest that bcl-2 protein is broadly expressed in various hematopoietic neoplasms not restricted in t(14; 18) lymphomas and that germinal center cells may be involved in some arrest of bcl-2 protein expression at the posttranscriptional level.

Blotting, Northern↗

R1-20, a novel monoclonal antibody reacting with a molecule distinct from integrin family, induces homotypic cell aggregation.

R1-20, a novel mAb reacting with a cell surface Ag on normal human lymphocytes and leukemic cell lines, was shown to induce homotypic cell aggregation in leukemic cell lines. This phenomenon was specific to mAb R1-20 because antibodies recognizing CD2, CD7, CD28, and HLA-ABC failed to exhibit homotypic cell aggregation. Induction of aggregation by mAb R1-20 occurred at 37 degrees C, but not at 4 degrees C and required cytoskeletal integrity. Sodium azide, a metabolic inhibitor, had no effect on the aggregation. Distinct from lymphocyte function-associated Ag-1/intercellular adhesion molecule-1 interaction in which divalent cations are essential elements, R1-20-mediated aggregation was not abolished with EDTA treatment. The R1-20 Ag was determined as a molecule of M(r) 100 to 110 kDa in immunoprecipitation and immunoblotting methods, under both reducing and nonreducing conditions. The molecular composition is quite different from that of any known integrin molecule. The R1-20 Ag was expressed on resting and activated T Lymphocytes as well as on normal B lymphocytes. Monocytes and granulocytes had no detectable R1-20 Ag. Among the leukemia-derived cell lines we used, mAb R1-20 reacted with 18 of 32 T cell lines, 2 of 20 B cell lines, 2 of 3 non-T-non-B cell lines, 2 of 7 myelomonocytic cell lines, and 2 of 3 nonlymphoid-nonmyeloid cell lines. All EBV-transformed B cell lines examined (10 cell lines) were R1-20+. The spectrum of reactivity among the cell lines tested was different from that of known antiadhesion antibodies tested. All these findings indicate that the Ag recognized by mAb R1-20 may represent a new type of cell adhesion molecule.

Antibodies, Monoclonal↗

Regulation of phospholipase A2 activation and arachidonic acid metabolism in an interleukin-3-dependent macrophage-like cell line.

An interleukin 3 (IL-3)-dependent macrophage-like cell line, 11-1-B3, was newly established from CBA/J mouse bone marrow cell cultures. Assay of eicosanoids in the culture supernatants of the intact and [3H]arachidonic acid (AA)-prelabeled cells showed that, after stimulation with the Ca2+ ionophore A23187, the 11-1-B3 cells synthesized and released relatively large amounts of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) but not LTC4. In addition, 11-1-B3 cells showed Ca(2+)-dependent and alkaline pH-optimal phospholipase A2 (PLA2) activity that preferentially hydrolyzed cleavage of sn-2-arachidonyl- but not sn-2-oleoylphosphatidylcholine. The cellular enzyme was distributed with 90% of the activity in the cytosol and 10% in the membrane fraction. Treatment of cells with A23187 for 5-10 min resulted in five- to sevenfold increases in the membrane-associated PLA2 but activity in the cytosol was unchanged. This increase in membrane-associated enzyme activity was transient, returning to the pretreatment distribution after 30 min. In sharp contrast, phorbol myristate acetate (PMA) stimulation failed to induce either eicosanoid release or PLA2 activation, although PMA induced translocation of protein kinase C (PKC) to the membrane fraction within 10 min. The data suggest that increases in cellular Ca2+ directly activate membrane-associated PLA2 and consequently initiate AA metabolism; PKC activation by PMA requires additional steps to activate PLA2, a mechanism that is apparently deficient in the IL-3-dependent M phi-like cells.

Animals↗

Effects of tumor necrosis factor alpha, interferon alpha and interferon gamma on non-lymphoid leukemia cell lines: growth inhibition, differentiation induction and drug sensitivity modulation.

The potential role of tumor necrosis factor alpha (TNF alpha), interferon alpha (IFN alpha) and interferon gamma (IFN gamma) in the therapy of non-lymphoid leukemia was studied in ten non-lymphoid leukemia cell lines. All three cytokines tested inhibited the growth of the cell lines. However, a high degree of variability in susceptibility to cytotoxic/cytostatic effect of the cytokines was found among individual cell lines. Some cell lines were sensitive to the antiproliferative action of only one of the cytokines tested, but were resistant to the others. Combinations of two cytokines had additive or synergistic effects and inhibited cell growth to a greater extent than did the individual cytokines alone. In addition to the growth-inhibitory effect, the cytokines induced an apparent cell differentiation. The differentiation of the two most sensitive cell lines, EoL-1 and PL-21, was confirmed using the nitroblue tetrazolium reduction test, by changes in cell morphology, immunophenotype marker profiles and by changes in c-myb expression. Furthermore, we showed that even in the cell lines relatively resistant to the antiproliferative effect of cytokines, such as cell line KCL-22, the inhibition of cell growth could be markedly increased with the DNA-topoisomerase-II-targeted drug, doxorubicin. Our data thus suggest that TNF alpha, IFN alpha and IFN gamma together have a potential role in the immunotherapy of non-lymphoid leukemia in terms of their antiproliferative action, and their ability to induce differentiation and to modulate drug sensitivity.

Cell Differentiation↗

Selective enhancement of interleukin 1 beta production in myelomonocytic cell lines by insulin and its related cytokines.

The production of interleukin 1 (IL-1) by lipopolysaccharide (LPS)-stimulated myelomonocytic cell lines ML-1, THP-1 and PL-21 was significantly enhanced by the addition of insulin, insulin-like growth factor (IGF)-I or IGF-II into the cell cultures. The IL-1 activity in the supernatants from cell cultures stimulated with LPS and insulin was completely neutralized by anti-IL-1 beta antibody. Anti-IL-1 alpha antibody had no inhibitory effect. Insulin itself did not stimulate IL-1 beta production directly, but increased it in the mitogen activated cells. However, insulin had no enhancing effect on the production of IL-1 alpha by human T cell lymphotropic virus-I (HTLV-I)-infected T cell lines or on IL-2 production by mitogen-stimulated leukemia T cell lines. Thus, insulin and its related cytokines are shown here as other molecules selectively modulating the production of IL-1 beta in myelomonocytic cell lines.

Human T-lymphotropic virus 1↗

Early phase II study of interferon-alpha and tumor necrosis factor-alpha combination in patients with advanced cancer.

Synergistic enhancement of anti-tumor effects through the combined use of natural human interferon-alpha (nHuIFN-alpha) and natural human tumor necrosis factor-alpha (nHuTNF-alpha) enabled us to decrease the effective dose of each cytokine and consequently to reduce side effects. One hundred and twenty patients with advanced or recurrent solid cancer were entered in the trial from April 1985 to January 1988, of whom 112 patients were evaluable. A mixture of nHuINF-alpha and nHuTNF-alpha was injected intravenously as the maintenance dose 1 x 10(6)U or more/day for over 8 weeks. There was no response in 40 patients injected with the maintenance dose of 1 x 10(6)U/day, but of 72 patients receiving more than 2 x 10(6)U/day (10 micrograms of nHuIFN-alpha and 3 micrograms of nHuTNF-alpha), 4 had complete responses, 10 had partial responses, and 4 had minor responses. The overall response rate was 12.5% (14/112) and the rate was 19.5% in 72 patients with more than 2 x 10(6)U/day. Positive responses were as follows: hepatoma 3/8), renal cell cancer (4/11), breast cancer (4/17), ovarian cancer (1/2), malignant thymoma (1/1) and liposarcoma (1/1). Serious adverse effects like hypotension, oliguria and severe hepatobiliary toxicity were never experienced. The effective and adequate dose of the mixed preparation was considered 2 to 4 x 10(6)U/day/body.

Adult↗

Historical progress and the future of human cell culture research.

Progress in human cell culture research is discussed based primarily on our hematopoietic cell culture studies. The article includes a historical background of Burkitt lymphoma cell lines, discovery of EBV, normal B-lymphoblastoid cell lines with EBV, a variety of leukemia, lymphoma, and myeloma cell lines, clinical and theoretical contributions made by studies of T-cell leukemia cell lines, the discovery and clinical relevance of HTLV, HIV and HBLV, early attempts at adoptive immunotherapy of patients with cancer, and the future of human cell culture research. Despite the fact that current cell culture methods permit maintenance of only limited cell types of both normal and malignant origins, biotechnological advances such as hybridoma and recombinant DNA technologies should continue to provide unlimited research opportunities in all fields.

Animals↗

Pediatric leukemia/lymphoma with t(8;14)(q24;q11).

A variety of chromosomal translocations occur in pediatric T-cell acute lymphoblastic leukemia (T-ALL) in which a cellular oncogene or growth-related gene is translocated to the alpha/delta locus of the T-cell receptor gene. The t(8;14)(q24;q11) has been described at the cytogenetic and molecular level, but the disease associated with this translocation has not been defined clinically. Fifteen pediatric cases of leukemia/lymphoma with a t(8;14)(q24;q11) chromosomal translocation were collected from previous publications and institutional records. The estimated prevalence of this abnormality among all cases of ALL was 1%. The t(8;14)(q24;q11) disease was characterized by male predominance (10/15), a median age of 5.5 years (range 1.8-17 years), high white blood cell count (median 95 x 10(9)/l), central nervous system infiltration (4/11), bulky extramedullary leukemia (10/11), and T-cell immunophenotype (12/15). The median event-free survival was 4 months, and the median survival, 11 months. Seven cell lines with t(8;14)(q24;q11) were established from six of the cases; four were T-lymphoblastic, one was T-lymphoblastic, but expressed myeloid-related antigens, and two were predominantly myeloid. t(8;14)(q24;q11) leukemia/lymphoma and other ALLs involving 13(q11) have in common a high tumor burden, early spread to extramedullary sites, a propensity to form T-lymphoblastic or T-myeloid cell lines and, usually, an aggressive clinical course.

Adolescent↗