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

Two adult patients with acute mixed lineage leukemia (AMLL) having combined Philadelphia chromosome (Ph1) positivity and monosomy 7 are presented. The phenotypes of leukemic blasts from both cases were almost same (early B-lymphoid lineage and myeloid lineage); CD10+, CD13+, CD19+. HLA-DR+, and dual-color analysis showed simultaneous expression of CD10 (CD19) and CD13 antigens in individual blasts (biphenotypic) in both cases. On molecular analysis, the leukemic blasts showed rearrangement in the first intron of the BCR gene with breakpoint just outside of 3' end of m-BCR-2 (bcr 3) in case 1, and in the M-BCR in case 2. Immunoglobulin heavy chain gene (IgH) rearrangement was noted in both cases, but rearrangement of the T-cell receptor beta-chain gene (TCR beta) was detected only in case 1. Clinically, both cases achieved complete remission by the combination chemotherapy consisting of L-asparaginase, doxorubicin, vincristine, and prednisolone (L-AdVP). In remission, all these molecular abnormalities disappeared in both patients. These results suggest that the Ph1-positive and monosomy 7 AMLL in adults is de novo acute leukemia with both early B-lymphoid and myeloid phenotypes and may arise from malignant transformation of pluripotent stem cell, and expresses a heterogenous rearrangement pattern of the BCR gene.
Leukemia 1993 Nov
PMID:Philadelphia-chromosome-positive, monosomy 7 biphenotypic acute mixed lineage leukemia in adults: a pluripotent stem cell disorder. 790 55

The myc proto-oncogenes encode nuclear DNA-binding phosphoproteins which regulate cell proliferation and differentiation. The c-myc gene is implicated in hematopoietic malignancies on the basis of its frequent deregulation in naturally occurring leukemias and lymphomas. Recent evidence suggests that also the N-myc and L-myc genes may have a role in normal and malignant hematopoiesis. N-myc and to a certain degree L-myc can substitute for c-myc in transformation assays in vitro, and their overexpression can block the differentiation of leukemia cell lines. Immunoglobulin heavy chain enhancer (IgH) -driven overexpression of N-myc or L-myc genes cause lymphatic and myeloid tumors, respectively, in transgenic mice. Furthermore, the L-myc and N-myc genes are expressed in several human leukemias and leukemia cell lines, L-myc predominantly in myeloid and N-myc both in myeloid and in some lymphoid leukemias. All N/L-myc positive leukemias and leukemia cell lines coexpress the c-myc gene, thus exemplifying a lack of negative cross-regulation between the different myc genes in leukemia cells. Taken together, these data suggest that L-myc and N-myc may participate in the growth regulation of hematopoietic cells.
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PMID:L-myc and N-myc in hematopoietic malignancies. 826 Aug 94

Immunoglobulin heavy chain (IgH) and T-cell receptor (TcR) genes can be monitored as markers of clonality by polymerase chain reaction (PCR) analysis in acute lymphoblastic leukaemia (ALL). We report the short clinical course of a 16-year-old patient with ALL and a t(4;11) who relapsed early following treatment and subsequently received reinduction chemotherapy followed by peripheral blood stem cell transplantation with interleukin 2 therapy. Despite this, the patient relapsed and died 8 months after presentation. The leukaemic cells were analysed by PCR and showed rearrangements of TcR V delta 2-D delta 3 and IgH CDRIII genes. Direct sequence analysis of the TcR delta and IgH PCR products revealed two leukaemic clones at diagnosis with one present at minimal levels. After initial therapy the major clone was no longer detected even in subsequent relapse samples but the originally minimal clone persisted and increased despite further treatment, indicating drug resistance.
Leukemia 1993 Jul
PMID:Clonal selection in acute lymphoblastic leukaemia demonstrated by polymerase chain reaction analysis of immunoglobulin heavy chain and T-cell receptor delta chain rearrangements. 839 15

Immunoglobulin heavy chain variable (V) gene replacement is an unusual recombinatorial event characterized by rearrangement of a germline V gene to a preformed VDJ gene complex. This phenomenon has occasionally been implicated in the emergence of clonal subpopulations during the course of acute lymphoblastic leukemia; it has also been found in murine precursor B cell lines. V gene replacement has never been described in lymphoproliferative disorders corresponding to more differentiated stages of B cell ontogeny. The present communication provides evidence for the operation of the same mechanism in B cell chronic lymphocytic leukemia (B-CLL). Genomic DNA and total cellular RNA extracted from peripheral blood mononuclear cells of a 48-year-old female patient diagnosed as having typical B-CLL were subjected to polymerase chain reaction (PCR) amplification aiming to detect rearranged clonal heavy and light chain variable genes (VH and VL, respectively). PCR consistently gave two VH amplification products, both at the DNA and the RNA level; similar analysis for the VL region revealed the presence of a single rearranged VK gene. Direct sequence analysis of the PCR products revealed that, except for a number of silent mutations, the single rearranged VK gene was identical to the germline A1-A17 VK gene. The two rearranged VH gene segments belong to the VHl and VHIII gene families and are closely homologous, respectively, to the germline gene segments V1-18 and V3-30, which have been shown to be used by autoantibodies. Both rearranged VH genes showed identical in-frame D-N-JH junctions and JH gene usage (JH5b), whereas the VH-N-D junctions were different. The above findings indicate that, during the course of the disease of our patient, VH gene replacement took place giving rise to two different clonally related subpopulations. This raises the intriguing possibility that the recombinase machinery, which governs Ig recombinatorial processes, might be operative even at more advanced stages in B cell ontogeny.
Leukemia 1996 Sep
PMID:Evidence for immunoglobulin heavy chain variable region gene replacement in a patient with B cell chronic lymphocytic leukemia. 875 79

Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of cases of B-lineage acute lymphoblastic leukaemia (ALL). We have examined bone marrow samples taken at presentation or relapse from 109 patients (79 adults and 30 children) and have performed sequence analysis of the complementarity determining region 3 (CDR3) on 65 alleles from 54 patients. We aimed to define immunoglobulin heavy chain (IgH) variable segment family use and investigate biological and structural features of the B cell in adult and childhood ALL. Using the FR1 fingerprinting method, a rearranged band was identified in 70 (89%) of 79 adult ALL and in 29 (97%) of 30 childhood ALL. This study found no preferential use or selection of IgH VH genes and no statistically significant structural differences between normal and leukaemic B cells in either adult and childhood ALL. An equal proportion of amplifiable cases of adult and childhood ALL uses more than one VH family gene (24/70, 34%, and 8/29, 27.5%, respectively). There were no significant differences in the structure or size of the CDR3 region and the variable (V) or joining (J) segment use in ALL patients compared to normal B cells. We observed that the N2 region was shorter than N1 in children whereas the opposite was observed in adults (not statistically significant). The J4 segment was a more common rearrangement in children than in adults, and in both groups J4 was more frequently associated with multiple D segment VDJ rearrangements. An increase in VH6 use in leukaemic alleles compared to normal B lymphocytes (2%) was observed but it was not statistically significant in our group of patients. Amongst children and adults, in-frame CDR3 junctions occurred in 78% and 64% of rearranged alleles, respectively, compared to 75% of in-frame sequences reported by others to occur among normal B cells.
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PMID:Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia. 882 93

Immunoglobulin heavy chain (IgH) oligoclonality in childhood B precursor acute lymphoblastic leukemia (ALL) as determined by Southern analysis is found in 30-50% of patients and has been shown to be the result of ongoing IgH rearrangement (mostly V(H)-replacement and V(H) to D-J(H) joining) after malignant transformation. It is unknown however, what determines the type of secondary rearrangement. Also the biological basis of the variable degree of oligoclonality observed in childhood ALL is poorly understood. We analyzed in detail the IgH rearrangement status of the leukemic cells for a random panel of 18 childhood B precursor ALL patients by polymerase chain reaction (PCR)/sequencing analysis and by Southern analysis. By Southern analysis 10/18 (55.6%) patients were considered oligoclonal and 8/18 (44.4%) monoclonal. In contrast, by PCR minor clonal rearrangements were detected in 14/18 (77.8%) patients. V(H)-replacement was found in 7/14 patients, V(H) to D-J(H) joining in 6/14 patients and an unusual type of secondary rearrangement, V(H)-D to J(H) joining, in one patient. Only a single type of secondary rearrangement was detected in each patient. The type of secondary rearrangement (V(H)-replacement or V(H) to D-J(H) joining) depended on the rearrangement status (VDJ/VDJ or VDJ/DJ, respectively) of the dominant leukemic clone as determined by Southern analysis. We found that in addition to a more 'advanced' IgH rearrangement status patients with V(H)-replacements also have a more 'advanced' TCRdelta rearrangement status, which possibly reflects exposure of both the IgH locus and the TCRdelta locus to recombinase activity in a preleukemic clone. Finally, we investigated a putative relationship between oligoclonality by Southern analysis and S-phase fraction of the leukemic cell population. We found a significantly lower percentage cells in S-phase for oligoclonal patients as compared to monoclonal patients. Our data add to the understanding of ongoing rearrangement of antigen receptor loci in childhood ALL and have implications for the monitoring of minimal residual disease by PCR.
Leukemia 1997 Aug
PMID:Rearrangement status of the malignant cell determines type of secondary IgH rearrangement (V-replacement or V to DJ joining) in childhood B precursor acute lymphoblastic leukemia. 926 79

Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of patients with B lineage acute lymphoblastic leukaemia (ALL). Two hundred and three bone marrow samples from 54 patients (33 adults and 21 children) were analysed by PCR within specific time-points after diagnosis (ie 1, 2-3, 4-6 and 7-12 months) using FR1 and JH primers (fingerprinting with a sensitivity > or =1:5 x 10[3]). CDR3-derived allele specific oligoprimers (ASO to achieve a sensitivity between 1:10[4] and 1:10[5]) were applied to 12 children and 18 adults, while size of CDR3 region, oligoclonality and background problems prevented their application to the remaining patients. All patients were followed clinically for > or =24 months. Thirty adults and 16 children presented as newly diagnosed ALL, while the remaining eight patients were analysed in first or subsequent relapse. Patients destined to relapse showed a higher proportion of positive tests (> or =50%), particularly after 1 month, than in the remission group, irrespective of age. Among patients staying in remission, a decrease in MRD-positive tests occurred during the first 12 months in both age groups. However, the proportion of positive tests dropped below 15% at a later stage in adults (4-6 months) than in children (2-3 months). Among children, only patients destined to relapse were MRD positive beyond 1 month, with the exception of only one patient, still positive at 2-3 months in the remission group. The difference in MRD positivity between relapse and remission patients was statistically significant in children (P < 0.03) at any time of testing, but only at 4-6 months in adults (P < 0.01). These data suggest that resolution of MRD in ALL occurs more rapidly in children compared to adults, particularly within the first 6 months. Children and adults, studied in first or subsequent relapse, showed a higher proportion of positive tests during reinduction compared to newly diagnosed patients.
Leukemia 1997 Oct
PMID:Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response. 932 95

Immunoglobulin heavy chain (IgH) gene rearrangement serves as a marker of clonality in B lymphoproliferative malignancies. In order to study the IgH rearranged gene in acute nonlymphoblastic leukemia (ANLL) patients we combine polymerase chain reaction (PCR) with Southern blot to detect 41 ANLL patients and 7 of them (17.1%) were found to have IgH rearrangement by PCR amplification. All these 7 positive cases were confirmed by Southern blot. The sensitivity of this method was 10(-4)-10(-5) level. In 12 patients with complete remission, 3 (25.0%) were found to have IgH rearranged gene. All these 3 cases had clinical relapse within 6 months. Our results show that IgH rearrangement not only may occur in lymphoblastic leukemia of B lineage, but also can be found in ANLL. The mechanism may be that in some ANLL patients, the leukemic transforming event might involve stem cells capable of both B cell and myeloid differentiation or ANLL might differentiate along different lineage with predominant appearance of one or the other subclone in the course of the disease.
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PMID:[Detection of immunoglobulin heavy chain (IgH) gene rearrangement in ANLL by polymerase chain reaction amplification and Southern blot]. 959 50

Chronic lymphocytic leukaemia (CLL) and hairy cell leukaemia (HCL) are chronic B-cell lymphoproliferative disorders (B-LPDs) with distinct clinical, morphological and immunocytochemical features. Transformation of CLL into other B-LPDs (prolymphocytic leukaemia (PLL) and large cell lymphoma) is a well recognised phenomenon. One previous report has suggested that HCL may also arise by clonal evolution from CLL. We report the case of a 75 year old man in whom a diagnosis of coexisting HCL was made seventeen years after an initial diagnosis of CLL. Immunoglobulin heavy chain rearrangement studies suggest that the two B-LPDs developed independently. A steady increase in the bone marrow HCL component at the expense of the CLL component was observed with time, suggesting that HCL may have a growth advantage over CLL.
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PMID:Coexistent hairy cell leukaemia and chronic lymphocytic leukaemia. 966 92

SJL mice are an inbred strain with a high incidence of spontaneous lymphomas of the B-cell type. We used molecular markers of clonality to study the process of tumor progression of SJL lymphomas in vivo. This was accomplished at time intervals ranging from 2 to 116 days by initial partial splenectomy (biopsy) followed by spleen sampling at the time of killing (autopsy). Immunoglobulin heavy chain (IgH) gene rearrangement and murine leukemia virus (MuLV) proviral integration patterns were used to study the clonal identities of the sequential tumor pairs in 11 informative mice by Southern blot hybridization. Of these 11 mice, 5 showed the same number of IgH gene rearrangement bands in the matched biopsy-autopsy samples, indicating the persistence of the original lesions. In 2 of 11 mice, a decrease in the number of IgH gene rearrangement bands was seen, consistent with a process of clonal selection in the original oligoclonal population. Another 2 of 11 mice showed an increase in the IgH gene rearrangement bands, indicating the emergence of either a new unrelated clone or, less likely, a subclone with secondary IgH gene rearrangement. The remaining two mice showed differences between the patterns in biopsy and autopsy samples, as assessed by IgH gene rearrangement and the proviral integration analysis. This finding suggests that the biopsied tumor had regressed and new clones had emerged. Tumor development was also associated with an increase in the number of clonal MuLV insertions in all mice except one, in which no non-germline integration band was detected. Of 11 mice, 5 showed an increase in the extent of tumor involvement by microscopic examination of the biopsy and autopsy samples; 3 showed a decrease, whereas 2 showed no change. A change in tumor morphology toward a more dedifferentiated appearance was found in only 1 of 11 mice. Overall, the results did not show a single paradigm that tumor progression followed, rather they indicated a complex and dynamic process of clonal evolution, which is likely to be a major feature of lymphoma progression in vivo.
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PMID:Progression of spontaneous lymphomas in SJL mice: monitoring in vivo clonal evolution with molecular markers in sequential splenic samples. 984 Jun 20


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