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PubMed2005

Genetic alterations in B-cell non-Hodgkin's lymphoma.

BACKGROUND: Although the patients with diagnosed B-NHL are classified into the same disease stage on the basis of clinical, histopathological, and immunological parameters, they respond significantly different to the applied treatment. This points out the possibility that within the same group of lymphoma there are different diseases at molecular level. For that reason many studies deal with the detection of gene alterations in lymphomas to provide a better framework for diagnosis and treatment of these hematological malignancies. AIM: To define genetic alterations in the B-NHL with highest possibilites for diagnostic purposes and molecular detection of MRD. METHODS: Formalin fixed and paraffin embedded lymph node tissues from 45 patients were examined by different PCR techniques for the presence of IgH and TCR gamma gene rearrangement; K-ras and H-ras mutations; c-myc amplification and bcl-2 translocation. There were 34 cases of B-cell non-Hodgkin's lymphoma (B-NHL), 5 cases of T-cell non-Hodgkin's lymphoma (T-NHL) and 6 cases of chronic lymphadenitis (CL). The mononuclear cell fraction of the peripheral blood of 12 patients with B-NHL was analyzed for the presence of monoclonality at the time of diagnosis and in 3 to 6 months time intervals after an autologous bone marrow transplantation (BMT). RESULTS: The monoclonality of B-lymphocytes, as evidenced by DNA fragment length homogeneity, was detected in 88 % (30/34) of B-NHL, but never in CL, T-NHL, or in normal PBL. Bcl-2 translocation was detected in 7/31 (22.6%) B-NHL specimens, c-myc amplification 9/31 (29%, all were more than doubled), K-ras mutations in 1/31 (3.23%) and H-ras mutations in 2/31 (6.45%) of the examined B-NHL samples. In the case of LC and normal PBL, however, these gene alterations were not detected. All the patients (12) with B-NHL had dominant clone of B-lymphocyte in the peripheral blood at the time of diagnosis while only in 2 of 12 patients MRD was detected 3 or 6 months after BMT. CONCLUSION: Because it is quic and simple, PCR analysis of clonal IgH rearrangements is very useful when diagnostic assistance is required. This technique is also very effecient for tracking minimal residual disease in lymphomas and leukemias and for monitoring clonal evolution in acute and chronic lymphoblastic leukemias and lymphomas. The presence of other genetic alterations, which we detected, should serve as an additional prognostic or predictive factor in the patients with B-NHL.

Gene Rearrangement, gamma-Chain T-Cell Antigen Rec↗
PubMed1990

Aggressive phase multiple myeloma: a terminal anaplastic transformation resembling high-grade lymphoma.

The term "aggressive phase" has been applied in multiple myeloma to the development of rapidly enlarging extramedullary soft tissue masses or of bone marrow transformation with histologic features resembling high-grade or anaplastic lymphomas. One hundred and one patients who fulfilled this definition were identified in a review of the literature. Eighty-six patients had soft tissue or visceral involvement and 15 bone marrow involvement. The mean age at initial diagnosis of myeloma was 53 years, suggesting that the aggressive phase may be more likely to develop in younger patients. A disproportionate percentage of these patients have an IgA gammopathy. Following the onset of the aggressive phase, these patients have a rapidly fatal course, refractory to therapy, with a mean survival of less than 3.5 months. It is hypothesized that this aggressive phase represents part of the natural history of multiple myeloma, analogous to the terminal transformations associated with other relatively indolent myeloproliferative and lymphoproliferative disorders. Studies are reviewed supporting the proposition that the clinical and morphological changes associated with the aggressive phase result from a clonal evolution of the original malignant cell line and do not represent the development of an independent new neoplasm.

Adult↗
PubMed2000

An in vivo and in vitro comparison of the effects of b2-a2 and b3-a2 p210BCR-ABL splice variants on murine 32D cells.

The Philadelphia (Ph) chromosome, a characteristic cytogenetic marker of chronic myeloid leukaemia (CML), is caused by a reciprocal translocation juxtaposing the 3' region of the ABL gene onto the 5' region of the BCR gene. Due to conservation of the reading frame, but depending on the site of the breakpoint in the BCR gene, two alternatively spliced variants of the p210BCR-ABL mRNA (known as b2-a2 and b3-a2) are produced. To investigate whether there are any biological differences between these splice variants we have transfected the b3-a2 or b2-a2 cDNA into a murine myeloid cell line, 32D. We have also included the previously prepared 32Dp210 cell line (which expresses the b3-a2 transcript) in all of our comparisons. RT-PCR analysis indicated that transcription levels were comparable between the variants. Morphological examination of the cells expressing either of the BCR-ABL transcripts indicated that these cells were more mature with increased cytoplasm:nuclear ratios compared to the 32D parental and 32Dneo vector control cells. However, the 32Dp210 cells had a very different appearance from the other panel members and flow karyotyping indicated a clonal evolution and cytogenetic instability in these cells alone. At 10(6) and 10(7) cell doses all 32D cells expressing BCR-ABL caused ill health and tissue infiltration in SCID mice with such rapidity that statistical analysis was not informative. However, at the 10(5) and 10(4) dosage levels there were similar survival rates between mice injected with 32Db2-a2 or 32Db3-a2 while mice injected with 32Dp210 had a significantly shorter survival time. The study of this 32D cell line panel indicated that there were no overt differences in the biological properties conferred by the b3-a2 or b2-a2 transcripts to the 32D cells although these transcripts were able to confer in vitro and in vivo biological effects. This panel of BCR-ABL expressing 32D cells provides a useful model for CML disease progression studies.

Alternative Splicing↗
PubMed2000

Acute myeloid leukemia with inv(8)(p11q13).

A patient with acute monoblastic leukemia (AML M5a) and the pericentric inversion inv(8)(p11q13) as well as additional chromosome abnormalities in her bone marrow cells is described. This is the fourth known case of inv(8)(p11q13)-positive acute leukemia, and the second such case in which gain of 1q material occurred during clonal evolution. All patients with acute leukemia and inv(8)(p11q13) have been females, most have been young, and there has been a tendency for the disease to run an aggressive course. Both hematologically and cytogenetically, therefore, inv(8)(p11q13)-positive leukemia may be viewed as a variant of AML with t(8;16)(p11;p13). This similarity is also apparent at the molecular genetic level, in-as-much as the MOZ gene in 8p11 is rearranged in both the translocation and the inversion; in t(8;16)-positive leukemia, a MOZ-CBP chimeric gene is generated, whereas inv(8) has been shown to generate a MOZ-TIF2 fusion gene. Southern blot analysis of the present case after MOZ0.8 hybridization of Bam HI digested DNA gave an 11 kb aberrant band in addition to the germline band, corresponding to a breakpoint immediately upstream of the 4 kb long MOZ exon that begins at position 3746. Also previously investigated inv(8)-positive leukemias have shown breaks in this intron indicating that it contains sequence motifs predisposing to illegitimate recombination.

Blotting, Southern↗
PubMed1993

CML: mechanisms of disease initiation and progression.

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of the myeloid lineage. It has a progressive course typified by the transition from the chronic phase to the accelerated phase and on to blast crisis. The hallmark of CML is the translocation between chromosomes 9 and 22 that results in the chimeric BCR-ABL gene encoding p210BCR-ABL. The oncogenic potential of this protein has been validated, and it is believed that it contributes in a critical way to the initiation of CML. However, the secondary genetic forces responsible for the transition from the chronic state to the fully blastic stage are not clear. Evidence for chromosomal instability includes the clonal evolution which characterizes advanced CML. In regard to specific genetic aberrations, sporadic reports have shown alterations in H-RAS, c-MYC, retinoblastoma, and P53 genes, as well as production of p190BCR-ABL during the progression of CML. In addition, we have recently found evidence for excessive interleukin-1 beta production, acting in an autocrine and/or paracrine manner, in the more advanced stages of the disease. Taken together, current data suggest that multiple molecular pathways lead to disease progression, and that distinct subsets of genetic alterations exist in blast crisis patients.

Blast Crisis↗
PubMed1994

Late clonal complications in severe aplastic anemia.

One hundred and seventy patients with severe aplastic anemia (SAA) were treated in Basel, from 1976 to 1992. Forty one underwent bone marrow transplantation (BMT) and 129 antilymphocyte globulin (ALG) therapy. As of January 1, 1993, 99 of the 170 patients are alive (58% +/- 7%) and the probability to be alive at 15 years is 54% +/- 4%. Until now, 29 patients have developed a clonal complication. All occurred within the ALG group. Nine patients developed a myelodysplastic syndrome (MDS), 16 patients paroxysmal nocturnal hemoglobinuria (PNH) and 4 patients both, PNH and MDS. The cumulative risk of developing a clonal complication after ALG-therapy is 42% +/- 13% at 15 years; for MDS this risk is 26% +/- 8% and for PNH 25% +/- 5%. The development of a clonal disease directly affects long term prognosis. The survival of the patients with stable disease is 81% +/- 10% and 36% +/- 13% for those with clonal evolution (p = 0.001). The most important risk factor is the type of treatment. In contrast to patients treated with ALG, none of the patients treated with BMT developed MDS or PNH (p < 0.001). No other clinical parameter, such as age, sex, etiology of SAA, severity of the disease and splenectomy correlate with an increased risk of developing this complication. In contrast, morphological parameters at the time of diagnosis, during bone marrow regeneration and at remission are indications in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

De-novo acute myeloid leukemia with trilineage myelodysplasia (AML/TMDS) and myelodysplastic remission marrow (AML/MRM).

Trilineage myelodysplasia (TMDS) in de novo acute myeloid leukemia (AML) at initial diagnosis and during remission has not been well recognized yet. In this review we describe the characteristics of de novo AML with TMDS (AML/TMDS) and with myelodysplastic remission marrow (AML/MRM) in view of the in vivo and in vitro disease progression. AML/TMDS was found in ten (10.4%) of 96 patients with de novo AML at initial diagnosis and AML/MRM were also observed in three (5.0%) out of 60 cases in remission after chemotherapy in our hospital between 1984 and 1992. Abnormal karyotypes were seen in six of nine AML/TMDS patients and all of the three AML/MRM. Karyotypic changes occurred in two of AML/TMDS and two of AML/MRM during their clinical course. Using the long term bone marrow culture (LTBMC) system that allowed abnormal clones to survive preferentially to the clone of normal karyotype, latent clones were detected in three patients with AML/TMDS and three of AML/MRM as in the cases of myelodysplastic syndrome (MDS) and AML transformed from MDS (MDS/AML) but not in the typical AML without myelodysplastic changes. Four of these cases exhibited the same karyotypes as seen during the clinical course. Primary abnormal karyotypes prior to clonal evolution were also observed in two of the AML/MRM. Taken together, both AML/TMDS and AML/MRM are similar to MDS/AML with respect to their myelodysplastic background and potential for disease progression and may have progressed to AML from the preceding disease status more rapidly than MDS/AML.

Acute Disease↗
PubMed1997

De novo acute myeloid leukemia with near-pentaploidy: diploid karyotype and lymphoblastic phenotype at relapse.

Hyperploidy is a rare finding in leukemias, with isolated cases of tetraploidy reported in acute myeloblastic and acute lymphblastic leukemias. We report the first case of acute myeloid leukemia with near-pentaploidy (5 n+/-) which was present in 100% of metaphases at diagnosis. By light microscopy, the leukemic blasts were exceptionally large and coarsely granulated. Following one cycle of induction chemotherapy, complete morphologic and cytogenetic remission was documented. Four weeks later relapse occured, at which time the karyotype was diploid and the morphological and immunophenotypic characteristics were those of a lymphoid leukemia. However, the presence of three aberrant chromosomes (5q+, 6q+ and 20q+) confirmed that this was clonal evolution of the original myeloid leukemia. To the best of our knowledge, this case represents the first report of near-pentaloidy in de novo, pretreatment human leukemia.

Acute Disease↗
PubMed1997

Chromosome 8 tetrasomies and pentasomies--a clonal abnormality closely associated with acute monocytic leukaemia.

We report four cases of polysomy 8 (one tetrasomy and three pentasomies) observed in acute monocytic leukemia (FAB M4 and M5). Three of them showed a rearrangement of 11q23 identified by conventional cytogenetic analysis and/or chromosome painting. Our cases as well as a review of the literature, suggest that polysomy 8 is preferentially associated with monocytic differentiation (24/31). These polysomies have been observed in 21 de novo leukemias and in 10 secondary hematological disorders. A 11q23 rearrangement has been detected in 9 out of 32 patients, by conventional cytogenetic techniques in 7 and by FISH in 2. We suggest that these cases should be analysed by FISH and molecular studies in order to detect a rearrangement of MLL/11q23. Monocytic differentiation is often associated with a change of the MLL gene and the polysomy 8 might be a particular clonal evolution secondary to 11q23 abnormality.

Adolescent↗
PubMed1998

Coexistent hairy cell leukaemia and chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) and hairy cell leukaemia (HCL) are chronic B-cell lymphoproliferative disorders (B-LPDs) with distinct clinical, morphological and immunocytochemical features. Transformation of CLL into other B-LPDs (prolymphocytic leukaemia (PLL) and large cell lymphoma) is a well recognised phenomenon. One previous report has suggested that HCL may also arise by clonal evolution from CLL. We report the case of a 75 year old man in whom a diagnosis of coexisting HCL was made seventeen years after an initial diagnosis of CLL. Immunoglobulin heavy chain rearrangement studies suggest that the two B-LPDs developed independently. A steady increase in the bone marrow HCL component at the expense of the CLL component was observed with time, suggesting that HCL may have a growth advantage over CLL.

Aged↗
PubMed1999

Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0).

Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To the best of our knowledge, only 19 such cases have been described in the literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2, three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one, myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF), one case each. Their median survival was 20 weeks. Here, we report the first case of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and intracellular MPO, but all lymphoid markers tested were negative. Conventional cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in addition to 15.1% with normal diploidy. However, Fluorescence in situ hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient died four weeks after diagnosis without therapy. In conclusion, these findings suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid disorders and heralds a bad prognosis. It may be a consequence of clonal evolution of trisomy 8.

Acute Disease↗
PubMed1999

The relationship between the myelodysplastic syndromes and the myeloproliferative disorders.

As a result of clonal evolution typical cases of one of the myelodysplastic syndromes may develop myeloproliferative features. Similarly, typical cases of one of the myeloproliferative disorders may develop dysplastic features, either as part of the natural history of the disease or as a result of exposure to mutagenic drugs or isotopes. There is also an important group of "overlap syndromes" in which cases, at presentation, have both dysplastic and proliferative features. Chronic myelomonocytic leukaemia and many cases of atypical chronic myeloid leukaemia, juvenile chronic myeloid leukaemia and the childhood monosomy 7 syndrome are "overlap syndromes". In addition, a significant minority of cases which fit the generally agreed criteria for a diagnosis of one of the myelodysplastic syndromes (refractory anaemia, refractory anaemia with ring sideroblasts or refractory anaemia with excess of blasts) also have thrombocytosis, neutrophilia, monocytosis, eosinophilia or basophilia.

Chromosomes, Human, Pair 7↗
PubMed2006

Mycobacterium bovis infection, Lyon, France.

In a 5-year retrospective study, we used spoligotyping and mycobacterial interspersed repetitive units to type 13 strains of Mycobacterium bovis isolated from human sources. Despite the relatively high incidence of human tuberculosis caused by M. bovis (2%), these tools showed no clonal evolution and no relationships between the isolates.

Adolescent↗
PubMed2026

Selective Inhibition of DNA Polymerase Proofreading: A Metabolic-Fidelity Mechanism Explains Agent Orange-Associated Myelodysplasia.

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint-selective inhibition of the proofreading exonuclease-thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell.

AMP↗
PubMed2026

Integrating Radiogenomics and CSF-Based Liquid Biopsy Sequencing for Precision Neuro-Oncology.

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood-brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling.

Humans↗
PubMed2003

Current mechanistic approaches to the chemoprevention of cancer.

The prevention of cancer is one of the most important public health and medical practices of the 21st century. We have made much progress in this new emerging field, but so much remains to be accomplished before widespread use and practice become common place. Cancer chemoprevention encompasses the concepts of inhibition, reversal, and retardation of the cancer process. This process, called carcinogenesis, requires 20-40 years to reach the endpoint called invasive cancer. It typically follows multiple, diverse and complex pathways in a stochastic process of clonal evolution. These pathways appear amenable to inhibition, reversal or retardation at various points. We must therefore identify key pathways in the evolution of the cancer cell that can be exploited to prevent this carcinogenesis process. Basic research is identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes are active during early development and are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes are mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. Thus there is a wide range of defects in cellular machinery which can lead to evolution of the cancer phenotype. Mistakes may not have to appear in a certain order for cells to progress along the cancer pathway. To conquer this diverse disease, we must attack multiple key pathways at once for a predetermined period of time. Thus, agent combination prevention strategies are essential to decrease cancer morbidity. Furthermore, each cancer type may require custom combination of prevention strategies to be successful.

Animals↗
PubMed1999

Multiple myeloma preceding the development of chronic myelogenous leukemia.

A case of a 70-year-old man who first developed multiple myeloma and then chronic myelogenous leukemia (CML) within a 3-year period is documented. The patient, with monoclonal hypergammopathy, was diagnosed with smoldering myeloma with IgG-kappa and Bence Jones protein kappa paraproteinemia. No chemotherapy was given for the myeloma until progressive leukocytosis developed after approximately 3 years. This was found to be due to Philadelphia chromosome positive CML. A reverse transcription-polymerase chain reaction assay did not reveal BCR/ABL mRNAs when the myeloma was first diagnosed. The occurrence of 2 distinct hematologic malignancies in the same patient suggests either a different clonal evolution from a common pluripotent malignant stem cell since the CML stem cell also involves the B-lymphoid lineage, a coincident complication of the 2 hematological malignancies, or the coexistence of 2 distinct malignancies due to the same genetic background and/or exposure to similar carcinogenic agents. The literature provides support for the existence of a relationship between multiple myelomas and CML.

Aged↗
PubMed1999

Evaluation of clonality in myeloid stem-cell disorders.

Clonality in myeloid stem-cell disorders can be determined using either indirect methods such as analysis of X-chromosome inactivation patterns (XCIPs), or detection of specific abnormalities such as the chromosomal translocations characteristic of myeloid leukemias. XCIPs are particularly useful for disorders lacking evidence of a specific marker. Most females can be studied using polymerase chain reaction (PCR) analysis of differential DNA methylation patterns in the human androgen receptor (HUMARA) or phosphoglycerate kinase (PGK) genes, and approximately 68% can be studied using transcription assays of three polymorphic genes, glucose-6-phosphate dehydrogenase (G6PD), iduronate-2-sulfatase (IDS), and p55. Studies are limited by the incidence of constitutive and acquired (age-related) skewing and results must be carefully interpreted with reference to appropriate control samples. These techniques have been applied to clonality status of hematological disorders, lineage involvement in a clonal process, and detection of clonal evolution.

Animals↗