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PubMed1995

Frequent ongoing T-cell receptor rearrangements in childhood B-precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease.

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.

Base Sequence↗
PubMed1990

Cytogenetics in the investigation of haematological disorders.

Chronic and acute, myeloid and lymphatic haematological neoplasms are characterized by acquired genetic rearrangements that, in the majority of cases, can be detected as clonal chromosomal abnormalities. The aberrations are either primary, meaning that they contribute to the establishment of the neoplasm, or secondary, in which case they are acquired during the clonal evolution and malignization of the neoplastic cells. The abnormalities are non-randomly distributed; the aberration pattern differs from disease to disease and sometimes is so characteristic that individual rearrangements may be virtually pathognomonic for particular neoplasms. The cytogenetic characterization of haematological malignancies is of two-fold importance. First, the recurrent aberrations provide us with an insight into the pathogenetic mechanisms that are operative. They pinpoint those areas of the human genome that carry genes or regulatory sequences whose function is disturbed in leukaemias and lymphomas. Using DNA recombinant techniques in addition to chromosome-level investigations of these cancer-associated rearrangements, the molecular pathology of leukaemias and lymphomas is now gradually being unravelled. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have a direct clinical importance. The finding of an acquired, clonal chromosome abnormality in haematopoietic cells (-Y in old men is an exception) means that the patient has a neoplastic disease. Often, but by no means always, the type of aberration is also informative as to which type of neoplasm is present. During therapy, remission and relapse can be monitored by cytogenetic analyses. Finally, the karyotypic pattern influences prognosis and may thus be taken into account when the choice of therapy is made.

Chromosome Aberrations↗
PubMed1991

Evidence for clonal disease by magnetic resonance imaging in patients with hypoplastic marrow disorders.

Some patients with hypoplastic marrow disorders, including aplastic anemia (AA), are at risk for clonal evolution to myelodysplastic syndromes (MDS) and leukemia. Magnetic resonance imaging (MRI) of marrow of the spine, pelvis, and femurs was performed in 24 patients with hypoplastic marrow disorders. In 12 patients (three AA, nine MDS) MRI was compatible with the clinical and biopsy diagnoses and served to define the spectrum of marrow patterns in these disorders. In eight patients with hypocellular marrow biopsies and a clinical diagnosis of AA, MRI showed an unexpected inhomogeneous or diffuse cellular pattern. Concurrent or subsequent marrow or cytogenetic studies have led to diagnoses of hypoplastic MDS in seven of these patients. In four patients with prolonged hypoplasia after bone marrow transplantation for lymphoma, a speckled pattern superimposed on a fatty background appeared in serial MRI studies. One case evolved to AML, two developed megaloblastic foci, and one remains hypoplastic at 19 months. This study suggests that MRI is able to detect early clonal disease in patients with AA, and can distinguish AA from hypoplastic MDS.

Adult↗
PubMed2001

Trypanosoma cruzi: presence of the two major phylogenetic lineages and of several lesser discrete typing units (DTUs) in Chile and Paraguay.

Multilocus enzyme electrophoresis (MLEE) of 99 Chilean and 11 Paraguayan stocks of Trypanosoma cruzi, the agent of Chagas disease, was performed for 22 variable genetic loci. As previously shown for this parasite in other geographic areas, a pattern of long-term clonal evolution of T. cruzi genotypes was inferred, both by strong departures of Hardy-Weinberg expectations and high linkage disequilibrium. The presence of the two major phylogenetic lineages that subdivide the species T. cruzi [Tibayrenc, M., 1995. Population genetics of parasitic protozoa and other microorganisms. In: Baker, J.R., Muller, R., Rollinson, D. (Eds.), Advances in Parasitology, vol. 36, Academic Press, New York, pp. 47-115; Souto, R.P., Fernandes, O., Macedo, A.M., Campbell, D.A., Zingales, B., 1996. DNA markers define two major phylogenetic lineages of Trypanosoma cruzi. Mol. Biochem. Parasitol. 83, 141-152], and of several lesser genetic subdivisions ('discrete typing units' or DTUs; Tibayrenc, M., 1998a. Genetic epidemiology of parasitic protozoa and other infectious agents: the need for an integrated approach. Int. J. Parasitol. 28 (1), 85-104; Tibayrenc, M., 1998b. Beyond strain typing and molecular epidemiology: integrated genetic epidemiology of infectious diseases. Parasitol. Today 14, 323-329; Tibayrenc, M., 1998c. Integrated genetic epidemiology of infectious diseases: the Chagas model. Mem. Inst. Oswaldo Cruz 93 (5), 577-580), was recorded in this region. Comparison between clonal populations in sylvatic and domestic transmission cycles of the disease in Chile strongly suggests that these two cycles are at least partially separated from one another.

Animals↗
PubMed1980

Evolution of cultured leukemic cell lines monitored by chromosomal and immunologic analysis.

We have investigated the karyotypes and markers of B lymphocyte differentiation in two leukemic cell lines, NALM-6-B and NALM-6-MI, both derived from a patient with non-T, non-B acute lymphoblastic leukemia. Both possess characteristics of thymus-independent, bursal-equivalent (B) lymphocytes. By means of immuno-fluorescence techniques, NALM-6-B was shown to possess 47% surface membrane immunoglobulin-positive (Slg+) cells, while NALM-6-MI is surface membrane immunoglobulin-negative (Slg-), but does possess cytoplasmic immunoglobulin M (ClgM+) in more than 90% of the cells. The Slg- ClgM+ phenotype, coupled with morphologic features, is consistent with NALM-6-MI being arrested at a stage early in B-lymphocyte differentiation (a "pre-B" cell). The predominant banded chromosome karyotype of NALM-6-B is pseudodiploid with a translocation of chromosomal material from the long arm of a chromosome 5 to the short arm of a chromosome 12 (5q-/12p+) and a marker Y chromosome. NALM-6-MI possesses the same marker Y chromosome and a deletion of the long arm of chromosome 5(5q-) since in most cells material missing from chromosome 5 does not appear on the short arm of chromosome 12. Within the limits of resolution available with the banding technique, no other karyotypic differences are observed in the two cell lines. The history of the two cell lines, the karyotypic analysis, and the pattern of immunoglobulin markers indicate the possible clonal evolution of NALM-6-MI from NALM-6-B and implicate a portion of the long arm of chromosome 5 in lymphoid differentiation of these leukemic cell lines.

Adult↗
PubMed1995

Localized gastric non-Hodgkin's lymphoma of high-grade malignancy in patients with pre-existing chronic lymphocytic leukemia or immunocytoma.

Analyses for clonality in cases of Richter's syndrome have provided evidence for a clonal evolution of high-grade lymphoma in most patients, while in others an independent cellular clone seems to exist in the secondary neoplasm. Richter's syndrome with an isolated high-grade lymphoma of the stomach has been rarely reported in patients with pre-existing B cell chronic lymphocytic leukemia (CLL). We investigated four cases of CLL or lymphoplasmacytoid immunocytoma (LPIC) with development of a localized high-grade B cell lymphoma in the stomach. Southern blotting showed different rearrangements of the immunoglobulin light and heavy chain genes in the tumor cells of the low-grade lymphoma and the gastric tumor in two cases. Comparison of the DNA sequences of the CDR3 region of the immunoglobulin genes revealed different clones in another case. By means of chromosomal in situ hybridization, trisomy 3 was detected in two cases of high-grade lymphoma of the stomach, but not in the cells of the associated low-grade tumor. Our findings indicate that high-grade non-Hodgkin's lymphomas arising localized in the stomach of patients with CLL or immunocytoma are not clonally related to the pre-existing low-grade lymphoma and, therefore indeed, present true secondary neoplasms.

Aged↗
PubMed1988

Clonal changes in tumours during growth and progression evaluated by southern gel analysis of random integrations of foreign DNA.

We have exploited random integrations of foreign DNA as a means of genetically tagging tumour cell populations with which to analyse the clonal evolution of tumour growth in vivo. Transfection of a non-metastatic mouse mammary carcinoma called SP1 (or a metastatic variant, SP1HU9L) with the pSV2neo plasmid or retrovirus vector infection with a "clipped-wing' vector (delta p delta eMoTN) was used to generate large numbers of uniquely marked tumour cell clones in single-step selections. The basic approach was to pool large numbers of independently marked transfectants or infectants, inject these cells into mice and analyse the resulting primary tumours and/or metastases later. Overgrowth or derivation of tumour masses by a limited number of clones could be detected by Southern gel analysis. The main findings were: (i) injection of pooled populations containing large numbers of uniquely marked cell clones (up to several thousand) invariably resulted in advanced primary tumours that contained a very limited number of clones, and in some cases only one easily detectable clone; (ii) primary tumours could be overgrown within six weeks by the progeny of the same single metastatic clone when the inoculum contained 1-10% metastatic cells, which suggests that metastatic SP1 cells have a selective growth advantage in primary tumours as well as for metastatic spread; and (iii) spontaneous lung metastases were clonal or biclonal at the time of analysis. The results show that spontaneous metastases can develop from a genetically distinct subpopulation of cells in a non-random (i.e. selective) manner. Because primary tumours can become overgrown by the progeny of a metastatic clone, results of any comparison of the properties of a primary tumour with a distant metastasis could be affected by the stage at which the primary tumour is removed and analysed.

Animals↗
PubMed1994

[Significance of chromosomal abnormalities in solid tumors of humans].

Solid tumours in man are characterized by acquired genetic rearrangements that, in most cases, can be detected by cytogenetic methods as clonal chromosomal abnormalities. Whereas primary abnormalities contribute to the establishment of the tumour and often are seen as solitary changes, secondary aberrations accrue during clonal evolution. Both abnormalities are nonrandom in distribution. Some primary abnormalities are so characteristic as to be virtually pathognomonic for particular types of solid tumours, eg, t (11;22)(q24;q12) in Ewing's sarcoma, t (9,22)(q22;q12) in extraskeletal myxoid chondrosarcoma, t (X;18)(p11;q11) in synovial sarcoma, and t (12;16)(q13;p11) in myxoid liposarcoma. To these purely cytogenetic data implicating specific genetic changes in carcinogenesis may now be added a growing evidence of molecular specificity emerging from recombinant DNA-studies. It appears that both currently known classes of directly cancer-relevant genes, the dominant oncogenes and the recessive tumour suppressor genes, are located at precisely those genomic sites that are visibly involved in neoplasia-associated chromosomal rearrangements. The importance of cytogenetic characterization of solid tumors is thus twofold. First, the recurrent aberrations provide insight into the pathogenetic mechanisms that are operative. They pinpoint areas of the human genome that carry genes or regulatory sequences whose function is disrupted in neoplastic cells. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have direct clinical importance. The finding of an acquired clonal chromosomal abnormality identifies the presence of a neoplastic disease, and the specific type of aberration may reveal the true nature of the tumor and thus improve the diagnostic precision.

Chromosome Aberrations↗
PubMed1998

Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin.

Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or "jumping translocations" of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.

Centromere↗
PubMed1995

Clonal dominance between subpopulations of mixed small cell lung cancer xenografts implanted ectopically in nude mice.

Clonal evolution of neoplastic cells during solid tumour growth leads to the emergence of new tumour cell subpopulations with diverging phenotypic characteristics which may alter the behaviour of a malignant disease. Cellular interaction was studied in mixed xenografts in nude mice and during in vitro growth of two sets of small cell lung cancer (SCLC) subpopulations (54A, 54B and NYH, NYH2). The tumour cell lines differed in cellular DNA content enabling flow cytometric DNA analysis (FCM) to be used to monitor changes in the fractional composition of the mixed cell populations. The progeny clone 54B was found to dominate the parent 54A clone when grown as mixed subcutaneous xenografts in nude mice, whereas no dominance was exerted during in vitro growth. The in vivo dominance could not be explained by differences in growth kinetics between the two tumour cell lines, and the interaction was not dependent on 54B being in excess in mixed tumours. The dominance was dependent on close in vivo contact as no remote effect on the growth of 54A was found when the dominating 54B cells were growing in the opposite flank of tumour-bearing mice. Irradiation inactivated 54B cells were unable to exert the dominating effect, indicating that the interaction required viable and proliferating cells. Clonal dominance was not found in mixed NYH-NYH2 tumours indicating that the dominance mechanism(s) may not always be operational between subpopulations in heterogeneous tumours. Recognition of interaction between tumour cell populations may result in a better understanding of the behaviour of heterogeneous human malignancies.

Animals↗
PubMed2026

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely because of its profound and evolving therapeutic resistance. Resistance is not determined by a single molecular alteration but arises from interconnected mechanisms, including intrinsic resistance, treatment-induced adaptive resistance, acquired resistance, genomic evolution, clonal selection, cancer stemness, phenotypic plasticity, metabolic adaptation, and tumor microenvironment-mediated effects. Emerging therapeutic approaches targeting KRAS/RAS signaling, stromal and immune components, metabolic dependencies, and DNA damage repair pathways offer opportunities to address these mechanisms, although durable efficacy remains limited by biological heterogeneity and adaptive responses. In this review, we examine therapeutic resistance as an evolutionary and multidimensional process and summarize emerging strategies for overcoming resistance. We further propose a Dynamic Precision Oncology (DPO) framework that extends conventional precision oncology beyond baseline molecular profiling by integrating longitudinal assessment of tumor genomics, circulating tumor DNA, CA19-9, imaging, radiomics, and clinical characteristics. This framework emphasizes iterative detection and characterization of emerging resistance, mechanism-informed treatment adaptation, and subsequent reassessment rather than automatic treatment modification based on a single biomarker. DPO may provide a conceptual framework for integrating evolving tumor biology into treatment decision-making, while prospective studies are needed to validate biomarkers, define actionable thresholds, and determine whether longitudinal resistance-guided strategies improve clinical outcomes in PDAC.

Humans↗
PubMed1996

11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone.

We report on 2 patients with acute leukemia who had an 11q23 chromosomal aberration as an additional change after treatment with etoposide and mitoxantrone, agents that affect topoisomerase II (Topo II). One patient with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (L2) received chemotherapy, including 1,000 mg of etoposide and 75 mg of mitoxantrone. She relapsed 10 months later. Analysis at time of relapse showed a chromosomal aberration of del(11)(q23) as an additional cytogenetic change. The other patient was diagnosed with acute monoblastic leukemia (M5a) and received two autologous peripheral blood stem-cell transplantations. Her cumulative doses of etoposide and mitoxantrone were 6,000 mg and 42 mg, respectively. She also relapsed, and analysis at that time revealed del(11)(q23) as an additional chromosomal aberration. The mixed lineage leukemia/myeloid-lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy-related leukemias caused by Topo II inhibitors. Based on these two cases, it may be that Topo II inhibitors can cause clonal evolution affecting chromosome band 11q23.

Adult↗
PubMed1999

Mutations in exons 5-8 of the p53 gene, independent of their type and location, are associated with increased apoptosis and mitosis in invasive breast carcinoma.

In breast cancer, mutations located in the zinc-binding functional domains of the p53 gene have been reported to predict a worse prognosis and a worse response to treatment with doxorubicin, compared with mutations in other parts within exons 5-8 of the gene. Similarly, mutations in residues of p53 that directly contact DNA have been associated with a poor prognosis. To investigate whether these specific p53 mutations are associated with differences in the rate of apoptosis and/or mitosis, or expression of the anti-apoptotic Bcl-2 protein, these parameters were evaluated in 89 invasive breast cancers with a confirmed p53 mutation in exons 5-8 and in 99 tumours without a p53 mutation in exons 5-8. Neither mutations located in the zinc-binding functional domains nor mutations in residues that directly contact DNA were associated with alterations in mitotic or apoptotic activity. However, compared with the wild-type p53 tumours, both apoptotic and mitotic indices showed an approximately two-fold increase in the mutant p53 group ( p< 0. 001). The presence of a p53 mutation was also associated with the presence of tumour necrosis ( p< 0.001), high tumour grade ( p< 0. 001) and low expression of Bcl-2 ( p< 0.001). Our data support the concept that in invasive breast carcinoma, loss of p53 function is involved in enhanced proliferation rather than decreased apoptosis and that the resulting acceleration of cell turnover may enhance clonal evolution and tumour progression.

Apoptosis↗
PubMed1996

Cytogenetic analysis of aggressive meningiomas: possible diagnostic and prognostic implications.

BACKGROUND: Published karyotypes from aggressive (atypical and malignant) meningiomas are few, but suggest clonal evolution from benign tumors with monosomy 22 to aggressive forms with additional abnormalities. The goal of this study was to identify the most frequent karyotypic abnormalities associated with aggressive histopathology and biologic behavior. METHODS: Eight intracranial meningiomas exhibiting histologically atypical features at the time of intraoperative diagnosis were chosen for cytogenetic analysis. The study set was comprised entirely of histologically atypical meningiomas. Four were considered malignant; three on the basis of brain invasion and one due to extracranial metastases. None was histologically anaplastic. RESULTS: Chromosomal abnormalities were demonstrated in 6 cases (75%), 5 of which were complex (63%). Loss of chromosome 22 was identified in two cases, both of which were associated with additional aberrations. Abnormalities most frequently involved chromosomes 1 (63%), 3 (50%), and 6 (63%). Four cases (50%) had dicentric or ring chromosomes. An additional 47 previously reported karyotypes from atypical and malignant meningiomas were reviewed. Comparison with published karyotypes of 200 histologically benign meningiomas served to underscore the increased frequency of complex karyotypes, chromosome 1, 3, and 6 abnormalities, and telomeric associations in the aggressive tumors. Apparently normal karyotypes as well as monosomy 22 alone were more frequently associated with benign, nonatypical histopathology. CONCLUSIONS: These findings suggest a possible role for cytogenetic analysis in determining the prognosis and perhaps in refining the diagnosis of atypical or aggressive meningiomas. Further studies are necessary to determine the significance of complex karyotypes, chromosome 1, 3, and 6 abnormalities, and telomeric associations, particularly whether they portend a more aggressive clinical course in meningiomas lacking features of histologic atypia.

Adult↗
PubMed1999

Transient monosomy 7: a case series in children and review of the literature.

BACKGROUND: Monosomy 7 and deletions of the long arm of chromosome 7 [del (7q)] are recurrent, nonrandom chromosomal abnormalities associated with both de novo and therapy-related myelodysplastic syndromes (MDS). The overall prognosis for children and adults with these chromosomal abnormalities is poor. In the current report, the authors present five children with MDS associated with monosomy 7/del(7q) who achieved spontaneous hematologic disease remission as well as a review of the literature. METHODS: Five children with either de novo or treatment-related MDS who achieved spontaneous hematologic disease remission are presented. Relevant clinical, cytogenetic, and fluorescent in situ hybridization data are included. RESULTS: All patients were boys. Three had de novo MDS whereas two others previously had received chemotherapy for another malignancy. Four patients achieved spontaneous and durable hematologic disease remission that was associated with cytogenetic disease remission in all three patients tested. The fifth patient developed a disease recurrence and died with evidence of clonal evolution after a long interval of hematologic and cytogenetic remission. CONCLUSIONS: A subset of children who develop MDS associated with monosomy 7 or del(7q) achieve spontaneous hematologic and cytogenetic improvement. Although this appears to be uncommon, further data are needed to determine the percentage of patients who improve without therapy and to define clinical characteristics that may predict this clinical outcome. These findings suggest that monosomy 7/del(7q) is insufficient to produce full leukemic transformation.

Adolescent↗
PubMed1999

Microsatellite instability and clonal heterogeneity of MDR1 messenger RNA expression in trimetrexate-resistant human leukemia MOLT-3 cells developed in thymidine.

Various gene alterations are involved in the drug resistance of leukemia cells. To understand the mechanism that underlies the emergence of cells with such gene alterations in human leukemia, we performed clonal analysis of the gene expression of mutant dihydrofolate reductase (DHFR) and mdr1 in trimetrexate-resistant human leukemia MOLT-3 cells. Trimetrexate-resistant (70- and 60-fold) sublines were developed in the presence or absence of an exogenous supply of thymidine (MOLT-3/TMQ70/Th+, MOLT-3/TMQ60/Th-, respectively). Ten clonal lines were isolated by methyl cellulose cloning from each of the 2 trimetrexate-resistant MOLT-3 sublines. All the clonal lines from the 2 sublines expressed mutated DHFR mRNA, with a base change (T --> C) at the second position of codon 31, as well as the wild-type mRNA, in accordance with cross-resistance to methotrexate. On the other hand, mdr1 mRNA expression was demonstrated by reverse-transcription polymerase chain reaction only in clonal lines from MOLT-3/TMQ70/Th+ cells. mdr1 mRNA expression in clonal lines from MOLT-3/TMQ70/Th+ cells and subclonal lines subsequently obtained from the 3 clonal lines with different mdr1 mRNA expression levels was heterogeneous, and its high expression levels were correlated with acquisition of the multidrug resistance (MDR) phenotype. Polymerase chain reaction-based assay for separate microsatellites, mfd27 and mfd41, demonstrated genomic instability among clonal and subclonal lines of MOLT-3. The clonal analysis of polymorphic microsatellites also suggested that emergence of MDR in trimetrexate-resistant MOLT-3 cells in thymidine was not only heterogeneous but also progressively expanding among clones. Genomic instability may play a role in the establishment and clonal evolution of drug resistance in leukemia cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

A novel 8-bp insertion in codon 281 of p53 in a patient with acute lymphoblastic leukaemia and 2 separate leukaemic clones. Mutations in brief no. 219. Online.

We report a novel p53 insertion in a case of aggressive acute lymphoblastic leukaemia in a 16 year old male, in which 2 separate leukaemic clones were previously identified by T-cell receptor sigma and immunoglobulin heavy chain gene rearrangement studies. Initial p53 mutation screening of blast cells from 29 patients with acute leukaemia by PCR-denaturing gradient gel electrophoresis showed that 2 had a silent codon 213 polymorphism and only the index case had a somatic mutation identified to be an 8 bp insertion in codon 281 (5'CCGGGGGG-3'). This insertion was associated with the second, more aggressive clone which underwent clonal evolution and became resistant to cytotoxic chemotherapy. With an allele-specific primer in PCR, we were able to demonstrate the presence of this clone as a minority at disease presentation, and in 2 of 3 collections of peripheral blood progenitor cells.

Adolescent↗
PubMed2001

High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of "Richter's syndrome".

Approximately 3% of patients with B-cell chronic lymphocytic leukemia (CLL) develop a high-grade large-cell lymphoma consistent with Richter's Syndrome. In most cases, these lymphomas are of B-cell origin and are believed to arise by clonal evolution from the CLL cells. We present a case of a patient with a 10-year history of B-CLL who developed an aggressive large-cell lymphoma, confirmed by immunophenotype to be of T-cell origin. We suggest that in patients with CLL, immunodysregulation can result in the proliferation of T cells, which may mutate and result in the development of a new malignant clone.

Antigens, CD↗