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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The follow up of minimal residual disease (MRD) in childhood B-precursor ALL by polymerase chain reaction (PCR) may be of help for further stratification of treatment protocols, to improve outcome. However, the clinical relevance of this approach has yet to be defined. We report the retrospective follow-up of MRD in bone marrow (BM) samples from 50 childhood B-precursor ALL patients by IgH/TCR delta PCR. Twenty-two patients remained in continuous complete remission (median follow-up 61 months), and 28 experienced relapse (median follow-up 75 months). Initial regression of MRD on therapy correlated with outcome. At the end of induction therapy 2/18 (11.1%) patients from the CCR group were PCR positive vs 10/16 (62.5%) from the 'relapse' group (P = 0.005). The presence of PCR detectable MRD predicted event-free survival independent of standard clinical and cytogenetical parameters. Also subsequent to first BM relapse, a correlation between MRD regression and outcome was observed. Six of eight patients who became PCR negative in the time period between relapse and bone marrow transplantation are in CCR, whereas 7/7 patients who remained PCR positive in this time period died (P = 0.006). In approximately 70% of evaluable patients, clinical relapse was preceded by recurrence of detectable MRD at time intervals of 3-18 months earlier and the recurrence of PCR positivity after a period of negativity was always followed by overt relapse. At relapse, the combined use of IgH and TCR delta probes reduced false negativity caused by clonal evolution to approximately 10%. This study shows that the evolution of PCR detectable MRD is an independent predictor of outcome.
Leukemia 1995 Oct
PMID:Prolonged persistence of PCR-detectable minimal residual disease after diagnosis or first relapse predicts poor outcome in childhood B-precursor acute lymphoblastic leukemia. 756 17

About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology. Changes of the immunophenotype, especially of the expression of immunoglobulin (Ig) have been documented less frequently. Multiple tumor samples of two patients with follicular lymphoma who developed tumor progression, were studied by Southern blot analysis for rearrangements of the Ig genes and the oncogenes BCL2 and MYC. In both patients, the general pattern of Ig gene rearrangements, especially of the Ig light-chain genes, and the structure of the t(14;18) breakpoint as assessed by the polymerase chain reaction (PRC) and fine restriction mapping, remained unaltered with time. However, both within the functional Ig heavy-chain allele and around the t(14;18) breakpoint, extensive secondary alterations took place. This indicates clonal evolution rather than the appearance of an independent lymphoma. In the first case with progression from follicular lymphoma to Burkitt's lymphoma 3 years after diagnosis, alterations were especially present 3' of the t(14;18) breakpoint. In the second patient with a change from follicular to diffuse centroblastic lymphoma 4 years after diagnosis, subsequent class switches from IgM to IgG and to defective IgH expression were accompanied by deletion of C mu sequences and a rearrangement of the MYC gene, respectively. Additionally, in both patients alterations in individual restriction sites occurred, which most likely were due to somatic mutations within both the functional IgH and translocated allele. Our data indicate that complex alterations of both the functional and non-functional IgH allele may accompany tumor progression and may erroneously suggest the appearance of independent clones by Southern blot analysis. It remains to be established whether these alterations are causative events or the consequence of genetic instability and clonal evolution.
Leukemia 1995 Oct
PMID:Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes. 756 20

Interleukin 7 (IL-7) stimulates proliferation of normal human and murine B cell precursor (BCP) cells in a distinct fashion, depending on the stage of maturation of the cells. For instance, the productive rearrangement of the immunoglobulin heavy chain gene has been demonstrated to be essential for the response of BCP cells to IL-7 as the single proliferation stimulus. IL-7 activates a receptor that consists of the IL-7R protein and the common gamma chain (gamma c). BCP acute lymphoblastic leukemia (BCP-ALL) cells variably respond to IL-7. Among 72 cases of BCP-ALL IL-7 activated DNA synthesis in 34. In four cases inhibition of DNA synthesis was seen. In the remaining 38 cases IL-7 exerted no effects. We determined whether this heterogeneity in IL-7 response could be correlated with parameters that could influence the IL-7 response. Firstly we show that, in contrast to the murine BCP cells, the IL-7 response of human BCP-ALL cells did not correlate with the status of IgH chain gene rearrangement and expression, nor with the rearrangement of IgL chain genes. Subsequently, it is demonstrated that IL-7R protein and transcripts as well as gamma c transcripts are equally present in the IL-7 responsive and nonresponsive BCP-ALL samples, indicating that the defective expression of these chains could not be held responsible for IL-7 response failures. Finally, we observed that kit ligand (KL), known to synergize with IL-7 in the most primitive stages of normal B cell development, did not enhance the IL-7 responses of BCP-ALL cells.
Leukemia 1995 Jun
PMID:Heterogeneity of proliferative responses of human B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells to interleukin 7 (IL-7): no correlation with immunoglobulin gene status and expression of IL-7 receptor or IL-2/IL-4/IL-7 receptor common gamma chain genes. 759 67

AKR mice are highly susceptible to development of spontaneous T-cell lymphoma. Thymus removal at the age of 1-3 months greatly reduces T-cell lymphoma. Lymphomas that have the characteristics of T- and/or B-cells occur sporadically in peripheral lymphoid tissues of old thymectomized AKR/J mice. These thymectomized mice were shown to carry dormant potential lymphoma cells. Transplantation of lymphoid cells from 8-12-month-old AKR/J mice, thymectomized at the age of 6 to 8 weeks, into intact or thymectomized young recipients yielded 80-100% Ly-1+ pre-B or B-cell lymphomas. In the AKR-Fv-1b congenic strain the Fv-1n allele of AKR/J mice was substituted with the Fv-1b allele, thereby limiting viral replication and spread of the endogenous N-tropic murine leukemia virus. As a result of this restriction in virus spread, AKR-Fv-1b mice develop a low spontaneous incidence (7%) of T-cell lymphomas and about 28% of Ly-1+ B-cell lymphomas at old age. In spleens of 15-18-month-old thymectomized AKR/J mice and intact AKR-Fv-1b mice, 30-60% of the B-cells were of the Ly-1+ B type. Analysis of the IgH locus in these normal old spleens and Ly-1+ B lymphomas indicated mono- or oligoclonality. One particular IgH rearrangement was identified in many individual old spleens and tumors. A second specific IgH rearrangement was found in some tumors. Possible mechanisms involved in the expansion of Ly-1+ clones and their progression into tumors are discussed.
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PMID:Analysis of Ly-1+ B-cell populations and IgH rearrangements in "normal" spleens and in lymphomas of AKR/J and AKR Fv-1b mice. 768 52

Using reverse transcription and the polymerase chain reaction (RT-PCR), we determined the level of expression of BCL-2/IgH in 18 follicular center cell lymphomas containing a t(14;18) translocation involving the major breakpoint region and five non-neoplastic lymph nodes. BCL-2/IgH transcripts were demonstrated in 16 follicular center cell lymphoma cases (five high, 11 low) and were not present in any of the five non-neoplastic lymph nodes. In the two follicular lymphoma cases in which BCL-2/IgH transcripts could not be detected by RT-PCR, PCR amplification of genomic DNA indicated this was not due to primer selection. In addition, non-expression was confirmed at the protein level by immunoperoxidase studies. We therefore conclude that these represent true negative cases. This is the first time primary follicular lymphoma cases have been quantitatively studied at the RNA level for expression of BCL-2. We conclude that RT-PCR is a sensitive method for determining levels of expression of this oncogene and may be useful in studying the involvement of BCL-2 in follicular lymphoma.
Leukemia 1993 Nov
PMID:Follicular center cell lymphoma with the t(14;18) translocation in which the rearranged BCL-2 gene is silent. 769 6

The detection of minimal residual disease (MRD) in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR) may turn out to be a powerful tool in the evaluation and guidance of therapy. Most previously described techniques are highly sensitive but also too laborious for application in a routine setting. Here we describe a technique based on the determination of IgH VHDJH and TCR V delta 2D delta 3 junctional regions by PCR/cycle sequencing analysis and hybridization of junctional region oligonucleotide probes in a standard liquid hybridization (LH) assay. We systematically analyzed the applicability of this simplified approach for the monitoring of MRD in a large patient group. IgH VHDJH and TCR V delta 2D delta 3 junctional regions were amplified from presentation bone marrow samples obtained from 53 childhood B-precursor ALL patients. The combined approach allowed the identification of at least one tumor marker for 49/53 (92.5%) of patients. A total of 75 oligonucleotide probes (54 DJH, 21 V delta 2D delta 3) was tested in the LH assay. Sensitivity range was 10(-2)-10(-5) and 10(-4)-10(-5) for DJH and V delta 2D delta 3 junctional region probes, respectively. A sensitivity of at least one malignant cell in 10(4) normal cells was obtained for 84.8% of evaluable patients, applying on average 1.1 IgH and 0.47 TCR delta probes per patient. Comparison to a method based on the use of initial PCR product as clone-specific probe showed that oligonucleotide LH was one log more sensitive in six of nine patients tested. The presented technique allows the monitoring of MRD with acceptable sensitivities in over 90% of childhood B-precursor ALL patients. Moreover, the technique is suitable for prospective patient studies in a routine setting as it is fast, reproducible and makes use of a standard hybridization protocol for different oligonucleotide probes.
Leukemia 1995 Jan
PMID:IgH/TCR delta PCR oligonucleotide liquid hybridization, a fast and sensitive assay for monitoring minimal residual disease in childhood B-precursor ALL. 784 21

We sequentially analyzed the immunoglobulin heavy chain variable (IgH V) region gene of leukemia cells obtained from a chronic myeloid leukemia (CML) patient who had three episodes of B-lymphoid crisis after bone marrow transplantation. Southern blot analysis using the JH probe showed different rearranged bands at each crisis, although the same rearranged bands of the BCR gene were observed. We amplified and sequenced the IgH V region gene of the leukemia cells by reverse transcriptase polymerase chain reaction (RT-PCR) using the primers corresponding to the consensus 5'VH and mu constant regions. The dominant leukemia clone at each crisis had a unique VH-D-JH rearrangement; VH4A (V79)-DLR2-J5 (clone-1), VH4B (DP70)-DK4-J6 (clone-2) and VH4A (V79)-DN4-J6 (clone-3) at the first, second and third crises, respectively. Further analysis by PCR amplification using the consensus 5'VH and clone-specific primers revealed that clone-1 underwent VH4-->VH3 replacement at the second crisis, and that clone-3 was already in existence at the first crisis. Moreover, the DN4-J6 joining clone, in which the sequence was the same as that of clone-3, was identified at the first and third crises by PCR amplification using primers corresponding to the region upstream of the DN4 segment and DN4-J6 boundary of clone-3. These observations suggest that multiple clones were generated from the progenitor cells of blast crisis, which were transformed at a very early stage of B-lymphocyte ontogeny, by continuing rearrangement mechanisms of the IgH genes, and that the dominant clone at each crisis was undergoing change.
Leukemia 1995 Feb
PMID:Continuing immunoglobulin heavy chain gene rearrangements in chronic myeloid leukemia with recurrent B-lymphoid blast crises after bone marrow transplantation. 786 62

The detection of residual leukemia cells in the bone marrow of patients during morphologic remission has been greatly facilitated by use of the polymerase chain reaction (PCR) to amplify leukemia-specific sequences. While the current PCR strategies for estimating the amount of residual leukemia claim a detection sensitivity of one leukemia cell amongst 10(5) or 10(6) normal cells, a rigorous assessment of the relative error associated with these techniques has not been presented. We have developed a method of estimating the amount of residual leukemia in remission marrows that is analogous to the limiting dilution assays used to determine the frequency of immunocompetent cells in a responder cell population. Using this method we measured the fraction of all-or-none (i.e. positive or negative) reactions of the PCR amplification of the leukemia-specific IgH gene rearrangement in replicate samples of serial dilutions of DNA obtained from diagnostic bone marrow specimens from 15 children with B-precursor acute lymphoblastic leukemia (ALL). A sigmoid curve representing the fraction of positive PCR reactions at a given dilution of leukemia DNA was found to be the best fit to the data. The narrowness of the log-linear region of this curve prevents the direct application of the analysis methodology that has previously been described for limiting dilution assays. However, the residual leukemia burden during morphological remission in these 15 patients and in two additional patients who experienced relapse could be estimated by the described dilution analysis method using the best-fit equation. Furthermore, the data generated for diagnostic, remission and relapse marrow samples exhibited a small interspecimen variation. The results suggest that this method can reliably estimate residual leukemia over a range of five orders of magnitude. Although the PCR reaction appears to be one of the most sensitive methods for detecting residual leukemia, all techniques based on this procedure, including our own, must exhibit limitations inherent to the amplification process. Our estimates or relative error suggest that a realistic limit for the PCR estimation of residual leukemia lies in the range of one leukemia cell per 10(5) normal cells. The suggested method is rapid, technically simple and relatively inexpensive. Furthermore, the principles that it is based upon can be applied to any PCR-based strategy.
Leukemia 1995 Feb
PMID:Accurate quantitation of residual B-precursor acute lymphoblastic leukemia by limiting dilution and a PCR-based detection system: a description of the method and the principles involved. 865 91

The nucleoside analog 2-chlorodeoxyadenosine (2-CdA) has recently emerged as a most promising treatment for hair-cell leukemia (HCL). The response rates are high regardless of prior therapy, and the duration of complete responses (CR) after a single course of treatment is longer than with any other therapeutic agent. We investigated the presence of minimal residual disease (MRD) in ten HCL patients treated in our institution with 2-CdA. The presence of residual leukemic cells was investigated in patients in CR following one course of treatment, using the polymerase chain reaction (PCR) and heavy-chain immunoglobulin genes (IgH), or TCR delta derived clonospecific probes. Eight patients achieved a complete remission after a single course of treatment, as evaluated at 6 months. Among these patients, seven are still in CR with a median follow-up of 12 months (range, 6-20 months) and one has relapsed after 15 months. Using PCR, all the evaluable patients remaining in CR showed persistent evidence of detectable MRD with no sign of decrease over the observation period. From this small series, we conclude that a single course of 2-CdA does not eradicate HCL and that persistence of residual leukemic cells appears to be common in patients in complete morphologic remission. Whether persistence of MRD will have an impact on long-term outcome, or whether HCL patients in morphologic CR with persistent MRD will remain so, is a matter of longer follow-up.
Leukemia 1994 Jul
PMID:A single course of 2-chloro-deoxyadenosine does not eradicate leukemic cells in hairy cell leukemia patients in complete remission. 791 13

A total of 96 peripheral blood stem cell harvests (PBSCH) were collected following standard chemotherapy from 27 patients with leukemia, lymphoma, and myeloma. Tumor molecular markers were analyzed in diagnostic samples by Southern blot [immunoglobulin heavy chain (IgHJ), T cell receptor (TcR) delta chain, TcR beta chain] and polymerase chain reaction (PCR) amplification [IgH, TcR delta, t(14;18) translocation] and found in 11 of 22 and 13 of 27 patients, respectively. At a sensitivity of 2 to 5%, Southern blot analysis failed to detect tumor in PBSCH. Using PCR with sensitivities of 10(-4) (IgH, TcR delta) to 10(-6) [t(14;18)] tumor was present in 34 PBSCH collected from five patients with acute lymphoblastic leukemia and two with lymphoma. In these patients, PBSCH collected after successive courses of chemotherapy remained consistently positive. However, no tumor was detected in 28 PBSCH from five patients with lymphoma and one with myeloma. Of eight patients who had bone marrow examined (six concurrently) within 3 weeks of PBSCH, one had tumor in the PBSCH but not in the bone marrow, and three had tumor in the bone marrow but not in the PBSCH, indicating a possible advantage in using PBSC for autologous transplantation in these patients. Although PBSC are an alternative source of stem cells to bone marrow and are considered to have a lower incidence of tumor contamination, the majority of PBSC in this study were positive by PCR analysis. PCR analysis was unable to determine if a positive result represents clonogenic cells capable of initiating relapse following transplant.
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PMID:Molecular detection of tumor contamination in peripheral blood stem cell harvests. 791 73


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