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PubMed1982

Clinical implications of cytogenetic studies in cutaneous T-cell lymphoma (CTCL).

Detailed cytogenetic studies were performed in 41 patients with cutaneous T-cell lymphoma (CTCL): four patients had limited plaques, 13 patients had generalized plaques, eight patients had cutaneous tumors, 16 patients had generalized erythroderma, and four additional patients, who had relatively benign chronic dermatosis, served as controls. Correlating the histologic and cytogenetic results in the various tissues, it was observed that 62% of the peripheral blood specimens were cytogenetically positive but only 49% were morphologically positive; in the lymph node the ratio was 80 versus 45%, and in the bone marrow, 6 versus 3%. These studies demonstrate that chromosome abnormalities are frequently detectable before morphologic changes become apparent. Chromosome banding preparations showed extensive and wide-ranging heteroploidy; the #1 chromosome was most frequently involved in structural abnormalities while chromosomes #11, 21, and 22 were most frequently involved in numerical abnormalities. These cytogenetic findings support the impression that CTCL is a disease whose various clinical manifestations represent a chronologic sequence, with the cytogenetic findings paralleling the clinical symptoms: patients with minimal chromosomal changes had the best survival and the more extensive the chromosome abnormalities, the more advanced the clinical disease. Clone formation was seen in eight patients and this phenomenon, along with hyperdiploidy and near-tetraploidy, was associated with a poor prognosis and short survival. We conclude that CTCL progresses from an early phase with extensive chromosomal abnormalities and lack of clone formation to a terminal phase with clone selection. Cytogenetic studies can, therefore, be of significant diagnostic and prognostic value in CTCL.

Adult↗
PubMed1995

Adult acute lymphoblastic leukemia at relapse. Cytogenetic, immunophenotypic, and molecular changes.

BACKGROUND: There have been published reports on cytogenetic, immunophenotypic, and molecular changes at relapse in childhood acute lymphoblastic leukemia (ALL) including lineage switch and secondary leukemia. There are limited data, however, on the cytogenetic, immunophenotypic, and molecular parameters of adult ALL at relapse. Because, as in children, the cytogenetic and/or immunophenotypic changes observed in adult ALL at relapse may have prognostic significance, the authors investigated the significance of such changes. METHODS: Fifty-three patients with relapsed adult ALL for whom cytogenetic, immunophenotypic, and/or molecular analyses were performed at diagnosis and at relapse were studied. Changes in any of the parameters at relapse were correlated with total survival and survival from the time of relapse. RESULTS: Of the 32 patients for whom cytogenetic studies were performed at relapse, 21 (66%) showed clonal cytogenetic changes, 40% of which were clonal evolution. None of these cases, however, showed two entirely different abnormal karyotypes at diagnosis and at relapse. The immunophenotypes showed occasional gain or loss of one or two surface markers, and the molecular genetic configurations for JH, JK, and the T-cell receptor beta were stable throughout the evolution of the disease. Patients with clonal evolution had a shorter overall survival than the rest of the group (P = 0.02). This difference, however, was not significant with respect to survival measured from the time of relapse. CONCLUSIONS: The most frequent changes in the biologic profile of adult ALL at relapse are shifts in the karyotype, with or without clonal evolution. Clonal evolution detected at relapse is associated with a higher frequency of unfavorable karyotypes at diagnosis and with a worse overall prognosis. However, survival from the time of relapse is similar in patients with and without clonal evolution.

Adolescent↗
PubMed2000

Twenty-four-color spectral karyotyping reveals chromosome aberrations in cytogenetically normal acute myeloid leukemia.

Multicolor spectral karyotyping allows simultaneous visualization of all human chromosomes and screening for chromosomal rearrangements without a priori knowledge of any abnormalities involved. Based on this potentially increased sensitivity, we investigated, in a preliminary manner, whether spectral karyotyping could detect cytogenetic aberrations in karyotypically normal leukemia. The test population was comprised of 28 cryopreserved, cytogenetically normal acute myeloid leukemia (AML) samples from patients registered to a randomized trial for previously untreated AML (SWOG 9031). Two normal and 12 samples with known cytogenetic aberrations were used to validate and establish the diagnostic accuracy of the spectral karyotyping assay and instrumentation in a clinical setting. Enumeration and region-specific DNA fluorescence in situ hybridization (FISH) probes verified discrepant results. In the validation data set, spectral karyotyping refined complex karyotypic rearrangements in six cases and defined the chromosomal origin of a "jumping" homogeneously staining region; however, the technology was less sensitive in the detection of subtelomeric rearrangements and double minute chromosomes. In the test population, spectral karyotyping identified previously undetected cytogenetic aberrations in two cases (7%) of karyotypically normal AML: a cryptic 11q23 translocation in 20/20 cells and a minor monosomy 7 clone in 3/21 cells (FISH, 10.5%). Both of these abnormalities are considered to confer a poor prognosis when based on classical cytogenetic prognostic criteria. As an adjunct to classical cytogenetics and standard FISH analyses, the additive resolution of spectral karyotyping, in particular, with chromosome paints spiked with subtelomeric and/or locus-specific probes, may allow significant gains to be made in diagnostic accuracy and recognition of genotype/phenotype prognostic relationships, and in defining underlying biologic mechanisms in cancer. Genes Chromosomes Cancer 28:318-328, 2000.

Acute Disease↗
PubMed2002

Renal cancer: cytogenetic and molecular genetic aspects.

To date, much progress has been made in the fields of cytogenetics and molecular genetics of renal tumors. The previous and recent findings have delineated the characteristics of the various tumors, particularly the cytogenetic and molecular differences that exist between papillary and nonpapillary clear cell renal cell carcinomas (RCCs). At the same time, new cytogenetic subtypes have emerged [e.g., t(X;1)] in subtypes of RCC, while in others (e.g., Wilms tumors) several new cytogenetic abnormalities and consequent molecular involvement have been found. In addition to Wilms tumor, papillary RCC, and clear-cell RCC, cytogenetic and fluorescence in situ hybridization analyses have been performed on several other tumors of the kidney, including chromophobic carcinoma, metanephric adenoma, collecting duct carcinoma, transitional cell carcinoma, congenital mesoblastic nephroma, and malignant rhabdoid tumors of the kidney. This review is therefore intended to present a concise update on the cytogenetic and molecular data on renal tumors, focusing mainly on the clinical usefulness of the findings reported in the literature.

Adenoma, Oxyphilic↗
PubMed2002

Apparently unrelated cytogenetic abnormalities among 462 probands referred for the detection of del(22q) by FISH.

Laboratory-based reports of the cytogenetic abnormalities detected during the course of testing for deletion del(22q) are scant. We report our findings from the testing with FISH of 462 patients suspected to have del(22q) between 1994 and 2000. Of these, 447 had a normal karyotype. An apparently unrelated cytogenetic abnormality was detected in 15 (3.2%). Two of these abnormalities involved reciprocal translocation with chromosome 22q and one of these showed del(22q) with FISH. The other abnormalities included sex chromosome aneuploidies and unbalanced rearrangements of various chromosomal segments. There was no commonality among these abnormalities and no correlation with other reported cases. Among those with a normal karyotype, an unexpected deletion of the control arylsulphatase A (ARSA) probe was found, providing a definite frequency of 1/262 for ARSA deletions among patients suspected to have del(22q). Of the 462 referrals, 48 (10%) had one or more additional diagnoses, and in this group, 4 (8%) had del(22q) and 2 (4%) had an apparently unrelated cytogenetic abnormality. The data highlight the importance of initial cytogenetic analysis in patients suspected of del(22q) and negates the use of interphase FISH screening by itself for del(22q). The finding of 3.2% unrelated cytogenetic abnormalities is noteworthy. FISH should be used in any structural rearrangement to ascertain if the relevant locus is deleted or not. The continued reporting of patients diagnosed with del(22q) found to have an unrelated cytogenetic abnormality will expand the phenotypic spectrum and possible gene mapping may refine phenotypic specificity.

Adolescent↗
PubMed2006

Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis.

BACKGROUND: Postpolycythemic (PV) and postthrombocythemic (ET) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for de novo myelofibrosis with myeloid metaplasia (MMM), which is also known as agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. METHODS: Diagnoses of PV and ET required fulfillment of the World Health Organization criteria for the diagnosis of MMM as well as an antecedent history of either polycythemia vera or essential thrombocythemia that was supported by bone marrow examination. Cytogenetic findings were classified as being either favorable (normal or isolated 13q- or 20q- clones) or unfavorable (presence of abnormalities other than 13q- and 20q-). RESULTS: The study population was comprised of 66 young patients (age <60 yrs) with sMF, including 37 patients with PV and 29 patients with ET. Multivariate analysis of parameters other than cytogenetics identified older age (P = .02), anemia (hemoglobin level <10 g/dL [P = .007]), and PV (P = .009) to be independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n = 31 patients), the presence of unfavorable cytogenetic abnormalities (i.e., clones other than 20q- and 13q-) became the only adverse prognostic factor for survival (P = .001). A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival, along with thrombocytopenia and anemia. CONCLUSIONS: The results of the current study suggest that cytogenetic findings might supersede AMM-derived prognostic scoring systems for predicting survival in patients with sMF.

Adult↗
PubMed1990

Uterine leiomyoma cytogenetics.

Uterine leiomyoma--a benign smooth muscle tumor--has recently been found to contain tumor-specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14-15;q23-24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one-third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra-myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors--leiomyosarcoma and rhabdomyosarcoma--are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13-15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exists also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13-15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor-specific rearrangement.

Chromosome Aberrations↗
PubMed1992

Correlation of cytogenetic analysis and loss of heterozygosity studies in human diffuse astrocytomas and mixed oligo-astrocytomas.

The aims of this study were to correlate cytogenetic studies and molecular genetic loss of heterozygosity (LOH) analyses in human astrocytomas and mixed oligo-astrocytomas, and to locate putative tumor suppressor genes on chromosome 10. Paired blood and tumor samples from 53 patients were analyzed. The tumors included 45 diffuse astrocytomas (39 grade 4, 4 grade 3, and 2 grade 2), 1 astroblastoma, and 7 mixed oligo-astrocytomas (2 grade 4, 4 grade 3, and 1 grade 2). By cytogenetic analyses the most common numeric chromosome abnormalities were +7, -10, -13, -14, -17, +19, -22, and -Y. The most common structural abnormalities involved chromosome arms 1p, 1q, 5p, and 9p. By LOH and dosage analysis the most common molecular genetic abnormalities were of chromosome arms 5p, 6p, 7q, 9p, 10p, 10q, 13q, 14q, 17p, and 19p. When the results of all methods were combined, the most commonly abnormal chromosomes were, in descending frequency, 10, Y, 17, 7, 13, and 9. In 80 percent of cases the cytogenetic and molecular genetic studies were concordant. LOH studies were more sensitive in detecting loss of genetic material than cytogenetic analyses and accounted for 60% of the discordant results. When there were structural abnormalities, such as translocations or inversions, cytogenetic analysis was more sensitive in detecting an abnormality than molecular genetic studies. In addition to the 24 tumors which appeared to lose an entire copy of chromosome 10, there were 10 tumors with molecular genetic or cytogenetic evidence of loss of only a portion of chromosome 10. The genetic analyses of these tumors suggest that there are 2 regions on chromosome 10 that may contain potential tumor suppressor genes. One lies distal to locus D10S22 from 10q22 to 10qter, and the other lies proximal to locus TST1 on the 10q arm near the centromere or on the 10p arm.

Adult↗
PubMed1984

Development of rodent peripheral blood lymphocyte culture systems to detect cytogenetic damage in vivo.

Peripheral blood lymphocytes (PBLs) offer many advantages for in vivo cytogenetic studies. They can be removed nonlethally from the animal allowing a subject to serve as its own control, permitting the analysis of cytogenetic damage over time. Furthermore, mature PBLs normally do not divide, and some populations are long-lived. Thus, they have the potential to accumulate DNA lesions during chronic exposures to genotoxicants. We have developed standard methodologies for the whole blood culture of rat and mouse PBLs to serve as models for determining the sensitivity of PBLs to cytogenetic damage. The cultures obtained with these protocols give reproducible results with high mitotic indices, stable baseline sister chromatid exchange (SCE) frequencies, and ample numbers of first-and second-division methaphases for scoring both chromosomal aberrations and SCEs. The methodologies have been especially useful for examining cytogenetic damage after inhalation exposures to toxicants such as ethylene oxide, formaldehyde, benzene, and nitrobenzene. Of these compounds, only benzene and ethylene oxide were found to induce significant dose-dependent increases in SCEs in PBLs. Also, dose-response curves have been obtained for several carcinogens administered by ip injection. These studies show that PBLs are sensitive indicators of the genotoxic effects of the carcinogens benzo (a)pyrene, 2-acetylaminofluorene, cyclophosphamide (CP), N-nitrosomorpholine, and ethylmethanesulfonate (EMS). In addition, because subpopulations of lymphocytes can be stimulated to divide using different mitogens, it has been possible to compare the sensitivity of murine B and T lymphocytes following in vitro and in vivo cyclophosphamide exposure. Once the sensitivity and selectivity of rodent lymphocyte cultures are determined, these assays should be valuable not only as a means for predicting which environmental agents could lead to increases in human cytogenetic damage, but also as a way to corroborate human cytogenetic studies.

Alkylating Agents↗
PubMed1993

Flow cytometric and cytogenetic analyses in human spontaneous abortions.

Cytogenetic and flow cytometric analyses were performed on 38 human spontaneous abortions in an attempt to obtain information on karyotype abnormalities and to compare the two approaches of analysis. In 19 cases, it was not possible to perform cytogenetic analysis because too long a time had passed between surgical sampling and cell culture, and in vitro culture failed. Of the 19 cases analyzed, 10/19 showed a normal karyotype and 5/19 showed a single trisomy (2/5 trisomies involved chromosome 16, 1/5 trisomy involved chromosome 18, 1/5 trisomy involved chromosome 20, and 1/5 was Klinefelter syndrome). Of the remaining 4/19 cases, 2/19 showed a polyploid condition (1 tetraploidy and 1 triploidy), 1/19 a double trisomy (chromosomes 13 and 21), and 1/19 a pentasomy of the sex chromosomes (49,XXXXY). Flow cytometric analysis was performed on all abortive samples. The samples were subdivided, when possible, into two portions conventionally named "amniotic" and "chorionic", using the amniotic membrane as an anatomical reference. Maternal blood lymphocytes were used as a diploid standard for each sample. In the 19 cases not analyzed by the cytogenetic approach, flow cytometric analysis showed 9 diploid and 10 aneuploid DNA distributions. In the remaining 19 cases, analyzed with both approaches, the comparison of DNA estimations using cytogenetic and flow cytometric analyses showed good agreement. In the cases with karyotype abnormalities, flow cytometric measurement provided evidence of an alteration of DNA content with respect to the diploid standard. Flow cytometric analysis showed a diploid distribution, whereas cytogenetic analysis revealed chromosomal abnormalities in only 4/19 cases. These discordant results could be related to mosaic conditions or maternal cell contamination. Moreover, cytogenetic and flow cytometric analyses were performed on 2 amniotic cell cultures, and concordant results were obtained. The results obtained suggest that a combination of these techniques is beneficial in attempts to obtain information about DNA content alterations, even when cultures fail, and in screening studies of human abortions.

Abortion, Spontaneous↗
PubMed1995

Case report of spontaneous remission of cytogenetic relapse of chronic myelogenous leukemia suggestive of progression to blast crisis after allogeneic bone marrow transplantation.

Detection of the chronic myelogenous leukemia (CML)-related marker, the bcr/abl m-RNA transcript, in blood or bone marrow of patients with CML in hematologic remission after allogeneic bone marrow transplantation (allo-BMT) may be associated with the presence of minimal residual disease but does not uniformly predict hematologic relapse. In contrast, when there is cytogenetic reappearance of the Philadelphia (Ph1) translocation [t(9;22)(q34;q11)] along with additional cytogenetic abnormalities, especially more than 2 years after BMT, progression to hematologic relapse and acceleration of CML usually occur. An exception to this rule may be our patient, who was a 29-year old white woman diagnosed with Ph1-positive CML by cytogenetics. She was initially treated with hydroxyurea. An allo-BMT was performed 4 months after the diagnosis, while the patient was still in the first chronic phase of her disease, her HLA-identical brother serving as bone marrow (BM) donor. The conditioning regimen for BMT consisted of cytosine arabinoside, cyclophosphamide, total body irradiation, splenic irradiation, and intrathecal methotrexate. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Her hospital course was unremarkable and without evidence of acute GVHD. Six months after transplantation, the patient had mild chronic GVHD and was treated with azathioprine and prednisone for 6 months. A year later, she recurred with mild chronic GVHD. She was treated with azathioprine alone for 5 months. Subsequently, she received cyclosporin A and prednisone for 8 months, with resolution of her symptoms. Serial BM cytogenetic studies showed normal male donor karyotypes 12 and 24 months after BMT. At 36, 42, and 50 months after BMT, reappearance of the Ph1 was noted along with some cells with additional cytogenetic abnormalities, including t(6;14)(p21;q32). The breakpoint involvement of 14q32, the heavy chain Ig locus, in the new clone may be indicative of B-lymphoid lineage-based evolution. The abnormal clones disappeared 56 months from BMT and remained absent through 69 months after BMT. The patient has remained in hematologic remission during her entire post-BMT course. Clinically, she continues to do well without immunosuppressants at presently 69 months after BMT. The reappearance of the Ph1 chromosome could be associated with the immunosuppressive therapy given for chronic GVHD. This case supports the concept that immunologic mechanisms may be important in the eradication of CML after allo-BMT, and even cytogenetic evidence of blast crisis CML may spontaneously remit after allo-BMT.

Adult↗
PubMed2005

In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies.

Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.

Acute Disease↗
PubMed1997

Cytogenetic analyses of a murine carcinoma cell line and six metastatic derivatives with different degrees of radioresistability.

We reported that a murine carcinoma (DEN3) an its six pulmonary metastases (M2, M4C, M4D, M4E, M4F, and M6) exhibited different degrees of radioresistability (In Vitro Cell. Dev. Biol.26:222-228; 1990). While the M2, M4C, M4E, and M4F cultured cells survived up to 2.5 Gy, the cells of DEN3 and M6 tolerated up to 5.0 Gy, and the M4D cells could withstand up to 10.0 Gy of X-irradiation. In the present investigation, the cytogenetic features of these cell lines were examined: (a) to determine the degree of cytogenetic heterogeneity among these cell lines, and (b) to investigate whether any association between the cytogenetic anomaly and the degree of radioresistability could be established. Heterogeneous cytogenetic aberrations were detected in all of the above lines. Karyotype analysis of the M4D and M6 cell lines displayed both numerical and structural abnormalities. The gain and loss of chromosomal copies were observed. Structural aberrations, such as translocation and deletion appeared in both cell lines. However, correlation between the cytogenetic abnormality and the degree of radioresistability was not demonstrated except for a dramatic reduction in one or more copies of the X-chromosome that occurred in 86% and 93% of the M6 and M4D cells, respectively. The results suggest heterogeneous cytogenetic aberrations among these cell lines and a possible association between the loss of X-chromosome and radioresistability of these tumor cells.

Animals↗
PubMed1993

Cytogenetic studies of composite lymphomas: monocytoid B-cell lymphoma and other B-cell non-Hodgkin's lymphomas.

Monocytoid B-cell lymphoma (MBCL) is a newly recognized, morphologically and immunologically distinct, low-grade B-cell neoplasm that may exist as a pure morphologic entity or as a component of a composite lymphoma. To determine whether cytogenetic abnormalities exist in cases of MBCL, fresh tissue from four lymphoma specimens in which MBCL was a substantial component were analyzed by classic cytogenetics; no pure MBCL cases were available for study. One monoclonal neoplastic population was found in each case by immunophenotyping studies and classic cytogenetics. Clonal cytogenetic abnormalities included -X or +X, t(14;18)(q32;q21), del(6q), t(11;14)(q13;q32), dup(12q), dup(1q), t(2;3)(q13;q29), and der(8)t(8;9)(p11.2;q13). The abnormal clone usually reflected the underlying lymphomatous process, namely, follicular lymphoma [t(14;18)], mantle cell lymphoma [t(11;14)], or small lymphocytic lymphoma (partial trisomy 12). There were no cytogenetic abnormalities common to all neoplasms. Taken together, the cytogenetic and immunologic data suggest that although MBCL may exist as a pure entity, it also may commonly represent a morphologic variant or a component of other primary lymphomatous processes.

Adult↗
PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗
PubMed1996

Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML).

Clinical and biological features have recognized prognostic significance in acute myeloid leukemia (AML). To evaluate the interaction of these variables and weighted effect on treatment outcome, prognostic variables from 96 previously untreated patients were analyzed for association with expression of the MDR1 gene product P-glycoprotein (Pgp), and effect on response to induction chemotherapy, progression-free survival and overall survival. Multivariate relationships were analyzed using six prognostic variables, including age, cytogenetic pattern, gender, CD34+ surface phenotype, AML type (de novo versus secondary) and Pgp. Univariate comparisons indicate that Pgp (P = 0.0001), cytogenetic pattern (P = 0.0004) and a Cd34+ phenotype (P = 0.0005) are predictive of primary treatment failure, whereas Pgp (P = 0.0001) had the greatest predictive value in multivariate analysis. Only cytogenetic pattern retained prognostic significance (P = 0.0143) for response to induction therapy after adjustment for Pgp. Although all variable except gender were associated with Pgp, specimens harboring the favorable karyotypic abnormalities t(15;17), t(8;21) and inv(16) exclusively lacked Pgp expression. In a multivariate model, both Pgp and cytogenetic pattern predicted response and overall survival, whereas secondary AML and cytogenetic pattern influenced remission duration. These findings indicate that cytogenetic has prognostic relevance that is independent of Pgp, and implies the presence of undefined biological mechanisms affecting chemotherapy resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Cytogenetic features of childhood acute lymphoblastic leukemia. A concordance study and a Pediatric Oncology Group study.

Cytogenetic analysis yields important objective information that has been shown to correlate with both patient response to therapeutic intervention and patient survival. Bone marrow samples are submitted to a common reference laboratory for cytogenetic analysis from children with newly diagnosed acute lymphoblastic leukemia (ALL) registered on frontline Pediatric Oncology Group (POG) therapeutic studies (classification 8600 series). A portion of the sample from the Texas Children's Hospital (Houston, TX) a POG affiliate, was also submitted to a local cytogenetics laboratory for analysis. This study retrospectively compares karyotypic data and methods from the Laboratory of Medical Genetics, University of Alabama at Birmingham (reference laboratory) with those of the Kleberg Cytogenetics Laboratory at the Baylor College of Medicine (local laboratory) over a 35-month period to evaluate the effect of differences in specimen procurement, handling, and laboratory methodology on yield of cytogenetic information. Each laboratory was able to identify clonal abnormalities in 72% of cases examined during the last year of the study. When these data were combined, the overall detection rate of clonal abnormalities was 87.5%. Utilizing the same bone marrow aspirate from 73 children, this study demonstrates that cytogenetic methodology significantly affects the yield of identifiable clonal abnormalities, while variables such as overnight shipping have no discernable effect. This study also supports the contention that central laboratory testing effectively yields information critical to ongoing large-scale research endeavors.

Adolescent↗
PubMed1993

Review of the cytogenetic changes in acute megakaryoblastic leukemia: one disease or several?

The karyotypes of 116 cases of acute megakaryoblastic leukemia (AMKL) were reviewed, including 43 pediatric patients with Down syndrome (DS) and 73 non-DS patients. DS patients with AMKL often had a history of transient leukemia or myelodysplasia with an early age of onset of AMKL (median 23 months). In these patients, the frequency of additional cytogenetic change (numerical or structural) was low, with 10 of the 43 DS patients showing no additional cytogenetic change. A second group of patients had t(1;22)(p13;q13) or other cytogenetic abnormality involving 22q13. These patients had no history of transient leukemia but showed very early onset of AMKL. In this group of patients, marked organomegaly was noted; these patients also showed few specific additional cytogenetic changes. The remaining AMKL patients had a median age of 30 years with much more frequent cytogenetic changes, including rearrangement of 3q21 and 3q26-27, trisomy 21, and other specific changes. Based on the karyotype and clinical data, we hypothesize that AMKL may represent at least three separate disease entities with different genetic alterations giving rise to similar, but not identical, disorders. Subclassification of AMKL on the basis of the cytogenetic changes in the leukemic cells appears to be justified.

Adolescent↗