Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of Philadelphia-positive (Ph) acute lymphoblastic leukaemia (ALL) in a 40-year-old male is presented. At diagnosis, 80% of bone marrow cells were Ph. Remission with normal blood counts was achieved but the marrow became hypercellular, indicating conversion to chronic granulocytic leukaemia (GCL). The Ph clone persisted with a variable percentage of Ph cells. He developed testicular relapse 38 months from diagnosis. The patient died when engraftment with a matched unrelated bone marrow transplant failed. Molecular investigation of DNA prepared from diagnostic and remission bone marrow and from testicular tissue in relapse revealed the same sized rearranged fragment of the BCR gene using a probe to the major breakpoint cluster region. This case confirms that testicular involvement due to infiltration of the testes by the original Ph leukaemic clone may occur as an unusual complication in Ph ALL. Conversion to chronic-phase GCL, a rare occurrence in Ph ALL, may have contributed to the unusually long survival.
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PMID:Testicular relapse in Philadelphia chromosome positive acute lymphoblastic leukaemia. 850 40

A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.
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PMID:Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: correlation with scaffold attachment regions and topoisomerase II consensus binding sites. 863 39

The MLL gene located at 11q23 is frequently disrupted by chromosomal translocation in a wide spectrum of newly diagnosed acute leukemias. Recently, it has become apparent that the MLL gene is very frequently disrupted by chromosomal translocations in patients with secondary leukemias associated with chemotherapeutic regimens incorporating topoisomerase II inhibitors. These secondary leukemias associated with topoisomerase II inhibitors (most commonly teniposide, etoposide, or doxorubicin) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors. We have identified a site within the MLL breakpoint cluster region (bcr) that is highly sensitive to double-strand DNA cleavage induced by topoisomerase II inhibitors. This finding is quite specific and highly reproducible. Although it was initially discovered in malignant lymphoblasts isolated from a patient receiving multiagent chemotherapy, this site-specific double-strand DNA cleavage can be induced in tissue culture using malignant cell lines as well as peripheral blood from normal individuals. Site-specific cleavage occurs in a significant fraction of cells using a variety of model systems, is both time and dose dependent, and can be induced with either doxorubicin or etoposide. This site-specific cleavage maps to the same region as a consensus topoisomerase II cleavage site within the MLL bcr. These results suggest that site specific cleavage within the MLL bcr induced by topoisomerase II inhibitors may be an early step leading to MLL translocations and secondary leukemia.
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PMID:Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. 905 51

We describe two patients with myelodysplastic syndrome (MDS) and the Philadelphia chromosome (Ph). The patients were 64- and 69-year-old men who were diagnosed as having refractory anaemia with excess of blasts. During the terminal phase, the MDS evolved to myeloblastic leukaemia. Chromosome analysis showed normal karyotypes mixed with metaphases containing a classic Ph chromosome t(9;22)(q34;q11). Surprisingly, molecular studies showed breakpoint cluster region rearrangement between exons e1 and a2, compatible with a p190bcr/abl breakpoint, as observed in acute lymphoblastic leukaemia. We discuss the correlation between MDS and acquisition of the Ph chromosome, and the occurrence of p190bcr/abl in MDS.
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PMID:p190bcr/abl rearrangement in myelodysplastic syndromes: two reports and review of the literature. 890 95

The clinical and biological significance of additional chromosome aberrations was investigated in a large series of 66 adult patients with Philadelphia (Ph) chromosome positive acute lymphoblastic leukaemia (ALL). Additional chromosome changes were observed in 71% of the cases. 9p abnormalities were identified in 26%, and monosomy 7 as well as hyperdiploid karyotypes 50 were both found in 17% of cases. 9p anomalies were characterized by a low complete remission (CR) rate (58%) and an extremely short median remission duration (MRD: 100 d). In patients with monosomy 7, the poor treatment outcome was confirmed (CR rate 55%: MRD 113 d). In contrast, all patients with hyperdiploid karyotypes 50 achieved CR, and the overall survival was superior to all other Ph-positive ALL patients except those without additional chromosome aberrations. Exclusive rearrangement of the minor breakpoint cluster region of the BCR gene and lack of coexpression of myeloid-associated antigens in cases with 9p anomalies as well as a high frequency of rearrangements of the major breakpoint cluster region of the BCR gene in patients with monosomy 7 (89%) further substantiated that additional chromosome aberrations may characterize distinct subgroups of Ph-positive ALL. Moreover, the necessity of the complementing use of chromosome banding analyses, polymerase chain reaction (PCR) assays, and fluorescence in situ hybridizations in the accurate identification of Ph-positive patients has become evident due to variant Ph translocations in 3%, and negative PCR assays in 4% of the cases.
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PMID:Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. 898 45

Fifty-six patients with de novo acute myeloid leukemia M4/M5 subtypes were studied for rearrangements of the mixed lineage leukemia gene, MLL (also called HRX, Htrx-1, or ALL-1). Ten patients (18%) showed rearrangements of the MLL gene, 9 in a major breakpoint cluster region within a centromeric 8.3-kb BamHI fragment, whereas rearrangement in one patient was the result of a direct tandem duplication of exons 2-6 of MLL. Analysis of sequences at the duplication junction revealed that the points of MLL fusion within introns 6 and 1 both lie within Alu elements. This suggests the involvement of Alu repeat mediated homologous recombination in MLL self fusion. For the 10 rearranged samples, cytogenetics analysis revealed a normal karyotype in 3, and 3 had abnormalities other than 11q23. Survival analysis of patients revealed no difference between those with rearrangement of MLL and those showing the germ-line configuration.
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PMID:MLL self fusion mediated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes. 898 51

We report the cloning and characterization of the entire AFX gene which fuses to MLL in acute leukemias with a t(X;ll)(q13;q23). AFX consists of two exons and encodes for a protein of 501 amino acids. We found that normal B- and T-cells contain similar levels of AFX mRNA and that both the MLL/AFX as well as the AFX/MLL fusion transcripts are present in the cell line and the ANLL sample with a t(X;11)(q13;q23). The single intron of the AFX gene consists of 3706 nucleotides. It contains five simple sequence repeats with lengths of at least 12 bps, a chi-like octamer sequence (GCA/TGGA/TGG) and several immunoglobulin heptamer-like sequences (GATAGTG) that are distributed throughout the entire AFX intron sequence. In the KARPAS 45 cell line the breakpoints occur at nucleotides 2913/2914 of the AFX intron and at nucleotides 4900/4901 of the breakpoint cluster region of the MLL gene. The AFX protein belongs to the forkhead protein family. It is highly homologous to the human FKHR protein, the gene of which is disrupted by the t(2;13)(q35;q14), a chromosome rearrangement characteristic of alveolar rhabdomyosarcomas. It is noteworthy that the t(X;11)(q13;q23) in the KARPAS 45 cell line and in one acute nonlymphoblastic leukemia (ANLL) disrupts the forkhead domain of the AFX protein exactly at the same amino acids as does the t(2;13)(q35;q14) in case of the FKHR protein. In addition, the 5'-part of the AFX protein contains a conserved hexapeptide motif (QIYEWM) that is homologous to the functionally important conserved hexapeptide QIYPWM upstream of the homeobox domain in Hox proteins. This motif mediates the co-operative DNA binding of Pbx family members and Hox proteins and, therefore, plays an important role in physiologic and oncogenic processes. In acute leukemias with a t(X;11)(q13;q23), this hexapeptide motif is separated from the remaining forkhead domain within the AFX protein. The predicted amino acid sequence of AFX differs significantly from the partial AFX protein sequence published previously (Genes, Chromosomes and Cancer, 1994, 11, 79-84). This discrepancy can be explained by the occurrence of two sequencing errors in the earlier work at nucleotide number 783 and 844 (loss of a cytosine residue or guanosine residue, respectively) that lead to two reading frame shifts.
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PMID:Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). 901 Feb 21

Fluorescence in situ hybridization (FISH) and the reverse transcription-polymerase chain reaction (RT-PCR) were used to examine a patient presenting with acute myelogenous leukemia (AML) FAB M2, and a complex t(4;9;22)(p14;q34;q11.2). The patient's clinical course was characterized by an aggressive leukemia, resistant to intensive therapy including allogeneic bone marrow transplantation. FISH analysis, using two chromosome painting probes and a BCR/ABL specific probe, confirmed the cytogenetic observation of a 22q11.2-->4p14 and a 4p14-->9q34 exchange, and revealed the presence of a 9q34-->22q11.2, respectively. In addition, RT-PCR demonstrated the presence of a BCR/ABL transcript derived from the major breakpoint cluster region (M-bcr) of the BCR gene. This transcript has been shown to generate an active 210 kDa tyrosine kinase protein more commonly observed in chronic myelogenous leukemia. Because the presentation of AML with this ABL-->BCR fusion product is a rare event, it would seem likely that the additional complex chromosomal rearrangement involving chromosomes 4, 9, and 22 played a role in the aggressive presentation and clinical behavior of this patient's leukemia.
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PMID:Complex chromosome 4, 9, and 22 rearrangement in a patient presenting with AML-FAB M2. 907 96

The ALL1 gene (also called MLL, HRX, or Htrx1) at the cytogenetic band 11q23 is consistently altered by chromosome rearrangements in acute leukemias (ALs) of early infancy, in ALs developed after exposure to topoisomerase (topo) II-inhibitory drugs, and in a small subset of de novo ALs in children and adults. Because exposure to natural or medicinal substances blocking topo II during pregnancy have been proposed as etiological agents for infant leukemia, we have compared the distribution of ALL1 gene breakpoints in infant leukemias with an altered ALL1 gene configuration to those in secondary leukemia associated with prior exposure to topo II targeting drugs and in reference to the major topo consensus binding site in exon 9. ALL1 gene breakpoint distribution was determined by Southern blot hybridization and/or reverse transcription-PCR of the ALL1/AF4 fusion cDNA in 70 patients. Using restriction enzyme analysis, the 8.3-kb ALL1 breakpoint cluster region was divided in a centromeric portion of 3.5 kb (region A) and telomeric portion of a 4.8 kb (region B). ALL1 breakpoint were located in region A in 8 of 28 (28.5%) cases of infant ALs, 16 of 24 (66%) cases of de novo ALs, and 0 of 5 cases of therapy-related (TR) ALs. Conversely, ALL1 breakpoints in region B were detected in 20 of 28 (71.5%) cases of infant AL, 8 of 24 (33%) cases of de novo AL, and 5 of 5 (100%) cases of TR AL (P = 0.002). These results were confirmed by direct sequencing of the ALL1/AF4 fusion transcript in 30 cases (19 infants and 11 child and adult de novo cases). The analysis of ALL1/AF4 junction types showed that children and adults with de novo leukemia had ALL1 breakpoints in intron 6 (9 cases) or intron 7 (2 cases), whereas breakpoints in infant cases were mainly located in intron 8 (14 cases) and less frequently in intron 6 (4 cases) and intron 7 (1 case). The difference in ALL1 breakpoint location between infant and noninfant AL patients with ALL1/AF4 fusion was statistically significant (P = 0.00005). These data demonstrated that infant and TR ALs share a similar biased clustering of ALL1 gene breakpoints, which supports the possibility that topo II inhibitors may also operate in utero and play a crucial role in the etiology of infant leukemia.
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PMID:Infant acute leukemias show the same biased distribution of ALL1 gene breaks as topoisomerase II related secondary acute leukemias. 923 Jan 94

We report a case of chronic myelomonocytic leukaemia (CMML), which transformed first into acute myeloblastic leukaemia (AML) and then into acute lymphoblastic leukaemia (ALL). In the AML and ALL phases, chromosome analysis showed a classic Philadelphia chromosome (Ph) t(9:22)(q34:q11). Molecular studies showed breakpoint cluster region rearrangement between exons e1 and a2 compatible with a p190(bcr/abl) breakpoint as observed in Ph-positive lymphoblastic acute leukaemia. The minor (m-bcr) rearrangement was also detected during complete remission. This observation supports a multistep pathogenesis of leukaemias, and that the p190(bcr/abl) breakpoint may influence the course of the disease.
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PMID:Successive transformation of chronic myelomonocytic leukaemia into acute myeloblastic then lymphoblastic leukaemia, both with minor-bcr rearrangement. 923 86


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