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PubMed2005

The kinetics of clonal dominance in myeloproliferative disorders.

To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSCs) have been experimentally defined. We determined the consequence if 1 HSC became able to survive without the support of a microenvironmental niche while the rest of its behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats, requiring mean times of 2.5 +/- 0.5 and 7.0 +/- 1.2 years, respectively (n=1000 simulations/species). In both species, when the number of neoplastic HSCs exceeded 0.5% of all HSCs, clonal dominance was inevitable. Our results can explain the absence of clonal myeloproliferative disorders in mice (lifetime, 2 years), are consistent with clinical observations in cats, and provide insight into the progression of chronic myelogenous leukemia (CML) in humans. They also demonstrate that competition for microenvironmental support can lead to the suppression of normal hematopoiesis as neoplasia evolves. Toxic or immunologic suppression of normal HSCs is not required.

Animals↗
PubMed1982

Evolution of Sézary syndrome in the course of hairy cell leukemia.

A patient with a history of "leukemia" for 19 yr and documented hairy cell (HC) leukemia for 10 yr developed mycosis fungoides and the Sézary syndrome. The manifestations of both diseases were diagnostic on clinical and pathologic grounds. Ultrastructural, immunohistochemical, and surface marker techniques proved the HC to have phenotypic characteristics of the T-helper subset of lymphocytes to which the Sézary cells (SC) also belonged. Both types of cells contained tartrate-resistant acid phosphatase. HC did not infiltrate the skin. SC did not contain ribosome lamellar complexes. Because of otherwise overlapping morphology and the apparent replacement of HC by SC, it is likely that the Sézary cells constituted a genetic variant of the original neoplastic clone represented by the hairy cells. Since the biologic and therapeutic implications of such clonal evolution may be important, subtle phenotypic changes should be looked for repeatedly in patients with these diseases.

Aged↗
PubMed2003

Genetic evolution of alpha fetoprotein producing gastric cancer.

BACKGROUND: Alpha fetoprotein (AFP) producing gastric cancer is an unusual form of aggressive adenocarcinoma with a complex histological picture, including enteroblastic and hepatoid differentiation. AIMS: To investigate the genetic events underlying the phenotypic diversity in AFP producing gastric cancer and the ability of these tumours to produce AFP ectopically. METHODS: Multiple foci from 19 AFP producing gastric adenocarcinomas were microdissected and loss of heterozygosity (LOH) analysis was performed with a panel of microsatellite markers on nine chromosomal arms. RESULTS: For informative cases, LOH was most frequently detected on 17p (100%), followed by 13q (88%), 3p (87%), 5q and 9p (80%), 11q (70%), 18q (58%), 16q (53%), and 8p (50%). The average fractional allelic loss was 0.72. LOH was detected either homogeneously throughout the microdissected foci, or only in some parts of the neoplastic foci for each case. Heterogeneous patterns of LOH indicated genetic progression and/or divergence in clonal evolution. Furthermore, in six cases with heterogeneous LOH of 13q, 13q LOH was restricted to immunohistochemically AFP positive neoplastic foci. CONCLUSION: AFP-GC arises as an aggressive clone with extensive LOH and high fractional allelic loss. The presence of heterogeneous patterns of LOH suggested that the AFP producing carcinoma foci might evolve through genetic progression and/or genetic divergence. Silencing of the crucial gene on 13q may be involved in the acquisition of the AFP producing phenotype.

Adult↗
PubMed1992

Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin.

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in "remission," ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in "remission." Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during "remission." Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

Adult↗
PubMed1993

Overrepresentation of chromosome 12p sequences and karyotypic evolution in i(12p)-negative testicular germ-cell tumors revealed by fluorescence in situ hybridization.

Human testicular germ-cell tumors (TGCTs) comprise a heterogeneous group of solid neoplasms. These tumors are characterized by the presence of a highly specific chromosomal abnormality, i.e., an isochromosome of the short arm of chromosome 12. At present, this i(12p) chromosome is found in more than 80% of TGCTs. Isochromosome 12p has also been observed in some ovarian and extragonadal germ cell tumors. In the remaining so-called i(12p)-negative TGCTs other abnormalities involving chromosome 12, mainly 12p, can be found. In order to establish whether 12p abnormalities other than i(12p) are a common phenomenon in TGCTs, a panel of 11 i(12p)-negative tumors was investigated using multicolor fluorescence in situ hybridization. All TGCTs examined appeared to contain chromosomal abnormalities involving 12p, resulting in a distinct overrepresentation of short arm sequences. In addition, indications were obtained for a clonal evolution in one of the tumors. Our data suggest that the occurrence of 12p abnormalities is a common phenomenon in i(12p)-negative TGCTs and that these abnormalities, analogous to i(12p), may contribute to the process of tumor development.

Chromosome Aberrations↗
PubMed1990

Evolving abundance and clonal pattern of human germinal center B cells during childhood.

Childhood is a critical period for the development of the memory B-lymphocyte repertoire necessary in protective humoral immunity. This study addressed the natural history of memory B cells based on the previous identification of germinal center and mantle zone cells as the probable precursor and mature memory cell populations, respectively. Using flow cytometric quantitation of these B-cell subpopulations in human tonsil, we found that germinal center cells were abundant (70% of tonsil B cells) during early childhood (2 to 3 years), but decline by early adolescence (8 to 14 years) to a low level (33%, P = .0003). To study the clonal evolution of these B-cell subpopulations, germinal center and mantle zone B cells were isolated using a preparative magnetic immunobead method, and analyzed using a novel polymerase chain reaction-based quantitative assay to measure the abundance of B-cell clones bearing certain rearranged VH subfamilies. Two VH subfamilies were informative: VH1N clones were uniquely deficient in germinal center B cells at the early age period, but became abundant in later childhood; and VH3L clones were absent among germinal center cells regardless of age. In contrast, B-cell clones bearing each VH subfamily were abundant in the mantle zone subpopulation throughout childhood. These findings suggest that the abundance and clonal pattern of germinal center B cells evolves during childhood, presumably due to changing antigenic or ontogenic processes. Moreover, the distinct clonal pattern of germinal center versus mantle zone B cells suggests that a major phase of clonal selection occurs after germinal center emigration.

Adolescent↗
PubMed1992

Cytogenetic analysis in the diagnosis of acute leukemia.

Acute leukemias 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 leukemia and often are seen as solitary changes, secondary aberrations accrue during clonal evolution. Both abnormalities are nonrandom in distribution. The pattern differs between acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) and from subtype to subtype. Some abnormalities are so characteristic as to be virtually pathognomonic for particular types of leukemia. The importance of cytogenetic characterization of leukemias is thus two-fold. 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 in hematopoietic cells identifies the presence of a neoplastic disease. The aberration profile may reveal whether the patient has ALL or ANLL and which subtype it is. Remission and relapse can be monitored by cytogenetic analyses. Finally, the karyotypic pattern is an independent prognostic parameter that should be considered when the choice of therapy is made.

Chromosome Aberrations↗
PubMed1990

Chromosome analysis of 31 Wilms' tumors.

Cytogenetic analysis was done on 31 Wilms' tumors, including 2 renal tumors of clear cell sarcoma type, using short term cultures of primary tumors and/or nude mouse passages. Nonrandom secondary chromosome abnormalities, in particular, were noted as evidence of clonal evolution. Apparently normal karyotypes were found in 5 Wilms' tumors, all in patients less than or equal to 22 months old, and in one clear cell sarcoma. Abnormal karyotypes were seen in 25 tumors (80%); 6 were pseudodiploid, 3 were hypodiploid, and 16 (52%) were hyperdiploid, of which 8 had a modal number of 47-49 and 8 had a modal number of 50-55. Nonrandom structural abnormalities involved 1p/1q, 11p, 7p/7q, 16p/16q, 12q, and 17p/17q. Nonrandom numerical abnormalities included +6, +8, and +18. Trisomy 12 was the most common abnormality, structural or numerical, seen in 52% of tumors (81% of the hyperdiploid). In 2 tumors the +12 was the only apparent abnormality; in 1 other tumor an i(12q) was seen, suggesting that +12 may have special significance in the clonal progression of Wilms' tumor. Informative karyotypes of 68 Wilms' tumors from other reports were reviewed and compared to results in this series.

Child↗
PubMedDate not supplied

The rat Nb2 lymphoma: a novel model for tumor progression.

Tumor progression of cancers is manifested by phenotypic property changes including development of hormone/growth factor independence and metastatic ability. The progression results from acquired genomic alterations leading to clonal heterogeneity and outgrowth of more aggressive and therapy-resistant sublines. Previously, a cultured rat "Nb2 lymphoma" cell line was established, whose viability depends critically on the hormone, prolactin, acting as the principal growth factor. By prolactin starvation, prolactin-independent sublines were generated which possessed the parent karyotype plus extra acquired chromosomal changes (clonal evolution). In this study, the parent line (Nb2-U17) and a cloned subline (SFJCD1) were compared for metastatic ability using single s.c. tumor transplants in Noble rats. Rats (22) bearing Nb2-U17 tumors showed no evidence of metastases at autopsy, even when tumors at implantation site reached a size of 9 cm (length + width). In contrast, rats (19) bearing SFJCD1 tumors showed multiple metastases (liver, kidney) when transplants exceeded 5 cm. This difference in metastatic ability may be related to the acquisition of an inversion in chromosome 1, i.e. inv(1)(q31q41). The 1q41 locus is adjacent to the reported H-ras-1 proto-oncogene locus (1q41-q42). In another subline, tetraploidization (flow cytometric analysis, karyotyping) occurred spontaneously following prolonged culturing (20 mo). Together, the parent Nb2 lymphoma line and its clonal derivatives provide a novel system for studying cellular and molecular mechanisms underlying tumor progression to the metastatic phenotype.

Animals↗
PubMed2003

Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique.

Recently, various mutations within the Abl sequence have been described that negatively affect imatinib binding to Bcr/Abl resulting in cellular resistance of chronic myeloid leukemia (CML) cells. So far, little is known as to whether these mutations are preexisting or develop under imatinib therapy as current mutation analyses are limited by a low sensitivity of approximately 1:2 (50%) to 1:5 (20%). By combining peptide nucleic acid (PNA)-based DNA clamping with a fluorescence hybridization probe assay, we developed a new and highly sensitive technique for the detection of known mutations within the Bcr/Abl kinase domain. With this approach we investigated 19 cases of CML refractory to imatinib treatment before and during therapy. By clamping of wild-type Abl through PNA we could effectively enhance the detection sensitivity for the Bcr/Abl mutations Thr315Ile, Glu255Lys, and Tyr253His such that 1 mutant cDNA molecule could be detected in 500 negatives (0.2%). We observed in one case that a Gly255Lys mutation was detectable before treatment. By DNA analysis of buccal swaps, a genetic polymorphism could be excluded. In two cases clonal evolution of known mutations developed gradually under treatment. In another case an initially detectable Tyr253His mutation disappeared after therapy onset but was again observed after 6 weeks of imatinib treatment. Preexisting and evolving Bcr/Abl mutations associated with an unfavorable prognosis could be safely detected by the presented technique. This may facilitate risk stratification in CML and may serve as a model for individualized molecular monitoring and therapeutic strategies in other malignant diseases.

Adult↗
PubMed1996

Towards a unified evolutionary genetics of microorganisms.

I propose here that evolutionary genetics, apart from improving our basic knowledge of the taxonomy and evolution of microbes (either eukaryotes or prokaryotes), can also greatly contribute to applied research in microbiology. Evolutionary genetics provides convenient guidelines for better interpreting genetic and molecular data dealing with microorganisms. The three main potential applications of evolutionary genetics in microbiology are (a) epidemiological follow-up (with the necessity of evaluating the stability of microbial genotypes over space and time); (b) taxonomy in the broad sense (better definition and sharper delimitation of presently described taxa, research of hidden genetic subdivisions); and (c) evaluation of the impact of the genetic diversity of microbes on their relevant properties (pathogenicity, resistance to drugs, etc). At present, two main kinds of population structure can be distinguished in natural microbial populations: (a) species that are not subdivided into discrete phylogenetic lineages (panmictic species or basically sexual species with occasional bouts of short-term clonality fall into this category); (b) species that are strongly subdivided by either cryptic speciation or clonal evolution. Improvements in available statistical methods are required to refine these distinctions and to better quantify the actual impact of gene exchange in natural microbial populations. Moreover, a codified selection of markers with appropriate molecular clocks (in other words: adapted levels of resolution) is sorely needed to answer distinct questions that address different scales of time and space: experimental, epidemic, and evolutionary. The problems raised by natural genetic diversity are very similar for all microbial species, in terms of both basic and applied science. Despite this fact, a regrettable compartmentalization among specialists has hampered progress in this field. I propose a synthetic approach, relying on the statistical improvements and technical standardizations called for above, to settle a unified evolutionary genetics of microorganisms, valid whatever the species studied, whether eukaryotic (parasitic protozoa and fungi) or prokaryotic (bacteria). Apart from benefits for basic evolutionary research, the anticipated payoff from this synthetic approach is to render routine and common-place the use of microbial evolutionary genetics in the fields of epidemiology, medicine, and agronomy.

Animals↗
PubMed2002

Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia.

A serious complication of aplastic anemia (AA) is its evolution to clonal hematologic diseases such as myelodysplasia (MDS) and leukemia, which is usually associated with the appearance of a cytogenetic abnormality in bone marrow cells. We present here an analysis of a cohort of 30 patients with otherwise typical AA in whom clonal karyotypic evolution was observed during frequent periodic marrow examinations. The actuarial risk for this complication has been estimated in other studies at around 15% at 5 years. Conversion from normal to abnormal karyotype occurred at a constant rate after initial diagnosis, with about 50% of cases developing within the first 30 months. Transient chromosomal abnormalities were infrequent. Clinically, AA patients with clonal cytogenetic patterns were heterogenous; a variety of karyotypic defects with numerical and structural abnormalities of chromosome 7 accounted for 40% of all cases followed by trisomy 8, structural and numerical abnormalities of chromosome 13, deletion of Y chromosome, and complex cytogenetic abnormalities. Unlike in primary MDS, aberrancies of chromosome 5 and 20 were infrequent. The clinical course depended on the specific abnormal cytogenetic pattern. Most deaths related to leukemic transformation occurred in patients with abnormalities of chromosome 7 or complex cytogenetic alterations or both. Evolution of chromosome 7 abnormalities was seen most often in refractory patients who had failed to respond to therapy. In contrast, trisomy 8 developed in patients with good hematologic responses who often required chronic immunosuppression with cyclosporine A (CsA), and survival was excellent. Although AA patients with monosomy 7 showed a similar prognosis to those with primary MDS, trisomy 8 in AA appears to have a more favorable prognosis than in MDS.

Adolescent↗
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↗
PubMed2006

Double-locus sequence typing using clfB and spa, a fast and simple method for epidemiological typing of methicillin-resistant Staphylococcus aureus.

Sequence-based epidemiological typing of methicillin-resistant Staphylococcus aureus (MRSA) has recently been promoted because it results in unambiguous data sets that can be organized in local and global databases. The replacement of previous typing methods, such as the highly discriminatory pulsed-field gel electrophoresis (PFGE), has been attempted with various markers and typing schemes, including spa typing and multilocus sequence typing. However, despite a number of advantages, none of these methods showed convincing evidence for performance in epidemiological typing comparable to that of PFGE. By using three sets of 48 MRSA strains comprising isolates that were (i) genetically highly diverse, (ii) genetically related, and (iii) obtained from long-term carriers, we analyzed the performance of the four highly polymorphic S. aureus markers: clfA, clfB, fnbA, and spa. Typeability, discriminatory power, in vivo stability, and evolution of these markers were compared to those of PFGE. Clearly, none of the markers alone could match the discriminatory power of PFGE (63 genotypes; index of discrimination of 0.96). Instead, this could be achieved by combining markers in pairs. We showed that by using only 3' partial sequences of approximately 500 bp, the majority of each marker's discriminatory power was displayed, and using the partial sequences, the best performance was obtained with the combination of clfB and spa (57 genotypes; index of discrimination of 0.94). Genetic changes were not observed for any of the sequence markers over a period of 3 years and in the case of partial sequences for a period of more than 4 years. This is in contrast to PFGE where changes occurred after several months. The genetic differences found between isolate pairs of long-term carriers and among highly related isolates indicated clonal evolution. A typing scheme based on 500-bp 3' partial sequences of clfB and spa is proposed.

Adhesins, Bacterial↗
PubMed2006

Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate.

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

Adult↗
PubMed2003

The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate.

OBJECTIVE: To describe clinical and laboratory features of a cohort of patients with chronic myelogenous leukemia (CML) who developed Ph(-), trisomy 8(+) metaphases while on treatment with imatinib mesylate. PATIENTS AND METHODS: Conventional cytogenetics and triple-color interphase fluorescence in situ hybridization were used to identify 5 of 310 studied patients who, on follow-up analysis, had Ph(-), trisomy 8(+) cells while on therapy. RESULTS: None of the 5 patients had cytogenetic evidence of clonal evolution at the start of treatment with imatinib. All patients developed grade 3 or 4 neutropenia and thrombocytopenia during treatment. The emergence of Ph(-), trisomy 8(+) metaphases was seen at 3, 6, 13, 16, and 18 months from the start of treatment and was present at multiple time points. The maximum number of trisomy 8 metaphases ranged from 25 to 50%. Concomitantly, all patients had a profound suppression of Ph(+) cells (ranging from 0 to 65%) as well as the appearance of normal metaphases, ranging from 6 to 55%. None of the patients has shown clinical or hematologic signs of progression to a more advanced phase of CML. CONCLUSIONS: While on treatment with imatinib mesylate a small group (less than 5%) of patients with CML developed Ph(-) trisomy 8(+) clone associated with pancytopenia. None of the patients developed clinical or hematological signs of progression to a more advanced phase of CML. These observations suggest that identification of trisomy 8 cells may represent clonal Ph(-) cells that were uncovered by treatment with a selective and potent inhibitor of Ph(+) cells.

Adult↗