Chromosome 21 abnormalities with AML1 amplification in acute lymphoblastic leukemia

Fluorescence in situ hybridization (FISH) studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker chromosomes to analyze the contribution of chromosome 21 in these markers. FISH with a chromosome 21 painting probe confirmed that chromosome 21 was involved in all three cases. FISH with YAC probes showed that the number of extra copies varied according to their location on chromosome 21. Attention was focused on the AML1 gene, which was present as five copies in most of the cells exhibiting the marker chromosomes. As controls, 11 cases of childhood ALL were studied with PAC probes covering AML1. The results agreed with the banded karyotypes in 10 patients. FISH uncovered a clone with four copies of AML1 which were only observed by FISH analysis of interphase nuclei in one patient. No point mutation was detected in exons 3-5, encoding the runt domain of AML1, in the three cases, suggesting an oncogenic role of wild-type AML1 amplification.     

Establishment of a new human cell line (EN) with TP53 mutation derived from endometrial carcinoma

We present a new cell line, EN, established from an invasive endometrioid adenocarcinoma of the uterine corpus in 50-year-old patient. The cells show rapid growth in culture with a doubling time of 24.4 hours and high migration activity. Monolayer-cultured cells were polygonal in shape and showed a tendency to pile up without contact inhibition. Subcutaneous transplantation of the EN cells into nude mice formed solid tumors that were histologically diagnosed as adenocarcinoma, whereas no metastasis was observed. Cultured EN cells produced tissue polypeptide antigen. Genetic and molecular analyses revealed high telomerase activity and estrogen receptor beta but not alpha expression. Using the polymerase chain reaction-single strand conformation polymorphism technique, we have screened EN cells for TP53 mutation in exons 5-8. A mobility shift was observed in this cell line in exon 8. A nucleotide insertion (CGT-->CAGT) was detected at codon 273, which resulted in a creation of a stop codon at codon 308. This cell line thus appears to represent the development of a more malignant clone with divergent receptor function and growth behavior, and provides us with an interesting new tool for the study of tumorigenesis in the human endometrium.     

Establishment and characteristics of a T-cell acute lymphoblastic leukemia cell line, JK-T1, with a chromosomal translocation between 8q24 and 14q13.

A human leukemia cell line, JK-T1, was established from the bone marrow of a 10-year-old boy with T-cell acute lymphoblastic leukemia. The origin of the leukemic cell line, JK-T1, was demonstrated by its chromosomal and immunologic similarity to the patient's fresh leukemic cells. Karyotypic analysis revealed 46,XY,del(6)(q?),t(8;14)(q24;q13),der(9)t(9;?)(q34;?). In JK-T1, neither rearrangement nor amplification of the c-myc gene was observed apparently because the breakpoint of chromosome 14 was not q11 but q13. JK-T1 was independent of interleukin 2 (IL-2) because of little production of IL-2, little IL-2 receptor (CD25) on the surface, and no response to exogenous IL-2. JK-T1 had lymphocyte function associated antigen-1 (LFA-1) (CD11a, CD18) on its surface and could adhere to the hematologic stromal layer. These characteristics of JK-T1 cell line are considered to be useful not only for evaluating the role of t(8;14) but also in studying the adhesion molecules of leukemia.     

AML1-ETO 阳性急性髓系白血病CD19 的表达及其预后的意义

目的:探讨CD19 在AML1-ETO 阳性急性髓系白血病(Acute myelogenous leukemia with AML1-ETO positive ,AML with AML1-ETO positive)患者中的表达及对预后的影响。方法:收集我中心2010 年1 月至2015 年12 月共66 例初治AML1-ETO 阳性AML 患者资料,回顾性分析CD19 表达与一般临床特征的关系及对生存期的影响。结果:AML1-ETO 阳性AML 患者初诊时CD19 的表达率为50.0%。CD19 阳性与阴性患者在年龄、性别、初诊时血红蛋白、血小板、骨髓原始细胞比例、染色体核型、基因突变无统计学差异(P>0.05)。CD19 阳性患者初诊时白细胞计数低于阴性患者,有统计学差异(P =0.027)。CD19 阳性患者总体生存率明显优于CD19 阴性患者(P =0.030),CD19 阳性患者无复发生存率较阴性患者高,但差异无统计学意义(P =0.105)。多因素分析结果提示CD19 阳性是AML1-ETO 阳性AML 患者OS 的独立预后良好因素。结论:CD19 阳性可能是AML1-ETO 阳性AML 患者预后良好的标志。     

AML1 amplification in a child with acute lymphoblastic leukemia

We report a case of de novo acute lymphoblastic leukemia with tandem amplification of the AML1 gene located in a chromosome marker that originated from chromosome 21 and a long event-free survival.     

Isolation of a novel TP53 target gene from a colon cancer cell line carrying a highly regulated wild-type TP53 expression system

We established a colon cancer cell line SW480-LOWTP53-1 carrying a wild-type TP53 transgene that is inducible under control of the lactose operon. Induction of this transgene by isopropyl-β-D-thiogalactoside (IPTG) arrests growth of the transfected cells. To investigate cellular responses related to the TP53 signaling pathway to induce growth arrest, we applied a differential display method to screen mRNAs isolated from this cell line and looked for genes whose expression was activated or suppressed after induction of wild-type TP53. Subsequent Northern blot analysis confirmed that expression of one novel gene was regulated by wild-type TP53. The cDNA, termed TP53TG1 (TP53 target gene 1), contained an open reading frame of 270 nucleotides encoding 90 amino acids. Under conditions of cellular stress (ultraviolet irradiation or exposure to bleomycin or cisplatin), expression of TP53TG1 was induced in a wild-type TP53-dependent manner, indicating that this gene is likely to play an important role in the signaling pathway of TP53 and may function in response to cellular damage. Genes Chromosomes Cancer 23:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Identification of ins(8;21) with AML1/ETO fusion in acute myelogenous leukemia M2 by molecular cytogenetics

A high percentage of cases of acute myelogenous leukemia (AML) of the M2 subtype show a rearrangement between the AML1 and ETO genes. The detection of the AML1/ETO fusion has clinical relevance because patients with this subtype have a good prognosis. We present the results of conventional and molecular cytogenetic studies in a patient with acute myelogenous leukemia French-American-British M2 classification, who had a complex karyotype involving chromosomes 8 and 21. Dual-color fluorescence in situ hybridization (FISH) using the AML1/ETO probe demonstrated a recombination of both genes on an add(8) chromosome. The use of other FISH probes (CEP8, c-myc and TEL21) and spectral karyotyping indicated that AML1/ETO fusion occurred as a consequence of a previously undescribed ins(8;21)(q22;q22.1q22.3).     

Shiga toxin 1 induces apoptosis in the human myelogenous leukemia cell line THP-1 by a caspase-8-dependent, tumor necrosis factor receptor-independent mechanism

Shiga toxins (Stxs) induce apoptosis in a variety of cell types. Here, we show that Stx1 induces apoptosis in the undifferentiated myelogenous leukemia cell line THP-1 in the absence of tumor necrosis factor alpha (TNF-alpha) or death receptor (TNF receptor or Fas) expression. Caspase-8 and -3 inhibitors blocked, and caspase-6 and -9 inhibitors partially blocked, Stx1-induced apoptosis. Stx1 induced the mitochondrial pathway of apoptosis, as activation of caspase-8 triggered the (i) cleavage of Bid, (ii) disruption of mitochondrial membrane potential, and (iii) release of cytochrome c into the cytoplasm. Caspase-8, -9, and -3 cleavage and functional activities began 4 h after toxin exposure and peaked after 8 h of treatment. Caspase-6 may also contribute to Stx1-induced apoptosis by directly acting on caspase-8. It appears that functional Stx1 holotoxins must be transported to the endoplasmic reticulum to initiate apoptotic signaling through the ribotoxic stress response. These data suggest that Stxs may activate monocyte apoptosis via a novel caspase-8-dependent, death receptor-independent mechanism.     

AML1 amplification in a case of childhood acute lymphoblastic leukemia

We report an 8-year-old girl with B-cell acute lymphoblastic leukemia (ALL). The blast cell karyotype at diagnosis included a marker chromosome revealed by fluorescence in situ hybridization to be a derivative of chromosome 21. A high level amplification of the AML1 gene was identified, but it disappeared upon complete remission. This rare but recurrent abnormality warrants research of B-cell ALL, especially when a marker chromosome is present in the blast cell karyotype.     

RCH-ACV: a lymphoblastic leukemia cell line with chromosome translocation 1;19 and trisomy 8

A cell line (RCH-ACV) was established from a bone marrow sample of a child with acute lymphoblastic leukemia (ALL). The cell line lacked Epstein-Barr virus nuclear antigen and exhibited a recently described nonrandom chromosome translocation, 1;19, thought to be associated with pre-B-ALL and poor prognosis. Banding studies confirm that the breakpoint of chromosome #19 occurs at p13.3. Cell surface marker analysis using a panel of monoclonal antibodies revealed markers consistent with common ALL phenotype. Although the cells did not show cytoplasmic immunoglobulin, studies of the immunoglobulin gene rearrangement confirmed the pre-B phenotype. This cell line could be of great value to studies of the role of the specific translocation 1;19 in the etiology of pre-B-ALL.     

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.     

Malignant counterpart of myeloid dendritic cell (DC) belonging to acute myelogenous leukemia (AML) exhibits a dichotomous immunoregulatory potential

Dendritic cells (DCs) play a central role in immune regulation. Some leukemic cells are argued to be malignant counterparts of DC because of their ability to differentiate into leukemic DC. We characterize DC-like leukemia homogenously expressing CD11c+CD86+ in acute myelogenous leukemia patients. They express the Wilms' tumor-1 antigen and common DC phenotypes (i.e., fascin+, CD83+, and DR+) directly. Purified leukemic cells produce interleukin-12 (IL-12) simultaneously with Fas ligand (FasL) and IL-6, which may suppress T cell-mediated immunity. These cells can elicit strong allogeneic T cell responses as well as induce tumor-specific CD8+ cytotoxic T cells, suggesting that they effectively present tumor-associated antigens. In contrast, they drive primary T cells toward apoptosis mediated in a tumor-specific way by a Fas-FasL interaction. Taken together, DC-like leukemia uniquely influences immune surveillance in contradictory ways, some of which may be involved in the mechanism of immune escape.     

Juvenile chronic myelogenous leukemia with abnormalities of chromosomes 4 and 5

A case of a boy with juvenile chronic myelogenous leukemia (CML) and independent clonal abnormalities of chromosomes 4 and 5 is presented. The characteristics and cytogenetics of CML are discussed, as is the involvement of chromosomes 4 and 5 in hematologic malignancies. The significance of these karyotypic findings in juvenile CML is explored.     

Polychemotherapy of acute myelogenous leukemia in a patient with acute intermittent porphyria

Summary The safety of drugs in hepatic porphyrias has largely been established by clinical experience, which is very limited in the case of antineoplastic agents. We administered three cycles of polychemotherapy consisting of daunorubicin, cytarabine and 6-thioguanine, and modified supportive care to a 33-year-old Turkish woman suffering from acute myelogenous leukemia. The urinary excretion of total porphyrins, porphobilinogen, and aminolevulinic acid was continuously monitored. Excreation of these metabolites was permanently elevated, but the values were comparatively low during cytotoxic therapy while peak values were recorded at the onset of fever during bone marrow aplasia; yet there were no clinical signs of porphyritic attacks at that time. A few potentially unsafe drugs were tolerated without an increase in porphyrin excretion. Although the susceptibility to drugs is highly variable in patients with hepatic porphyrias, the treatment of malignancy in these patients seems justified as long as porphyrin excretion under therapy is not grossly elevated over baseline values and appropriately modified supportive care is administered.Abbreviations AIP Acute intermittent porphyria - ALA Aminolevulinic acid - CR Complete remission - DAT Daunorubicin, cytarabine (Ara-C), 6-thioguanine - FAB French, American, British classification - PBG Porphobilinogen - Po Porphyrin - RBC Red blood cells