Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR/ABL fusion gene in 31 patients with chronic myeloid leukemia (CML) was detected by RT/PCR. In 18 cases of Ph' positive patients, 13 had BCR 3/ABL II rearrangement, 1 had BCR 2/ABL II rearrangement and 4 had both rearrangements. One case with complex translocation: 46,XY,t(9;9;22), had BCR 3/ABL II rearrangement. In 8 cases of Ph' negative patients, 4 had BCR 3/ABL II rearrangement, 3 had both rearrangements while 1 had no BCR/ABL rearrangement. Interestingly, in 4 patients who had no cytogenetic result, we could observe BCR 3/ABL II rearrangement in 3 cases and both rearrangements in 1 case. The results suggest that this procedure is sensitive and independent of the presence or absence of an identifiable Ph' chromosome.
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PMID:Detection of BCR/ABL fusion gene in CML: a preliminary report. 862 6

A chronic myelogenous leukemia (CML) patient with a masked Ph chromosome due to the translocation (9;10;22)(q34;q24;q11) is reported. Banding analysis showed a 9q+ chromosome typical of standard t(9;22)(q34;q11), and fluorescence in situ hybridization studies confirmed the involvement of a chromosome 10 in the masked Ph formation and also the presence of 3' ABL-DNA sequences in the der(22). This complex rearrangement could be explained by two consecutive translocations: the first, a standard t(9;22) (q34;q11), the second, a translocation between a chromosome 10 and the der(22) with a breakpoint in sequences derived from chromosome 9 telomeric to the ABL gene. By reverse transcription polymerase chain reaction (RT-PCR), we studied the BCR/ABL transcript junction: a chimeric m-RNA b3-a2, indicating a breakpoint within the major breakpoint cluster region, was found.
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PMID:Fluorescence in situ hybridization provides evidence for two-step rearrangement in a masked Ph chromosome formation. 863 61

Chronic myelogenous leukemia (CML) and some acute lymphoblastic leukemias (ALL) are caused by the t(9;22) chromosome translocation, which produces the constitutively activated BCR/ABL tyrosine kinase. When introduced into factor dependent hematopoietic cell lines, BCR/ABL induces the tyrosine phosphorylation of many cellular proteins. One prominent BCR/ABL substrate is p120CBL, the cellular homolog of the v-Cbl oncoprotein. In an effort to understand the possible contribution of p120CBL to transformation by BCR/ABL, we looked for cellular proteins which associate with p120CBL in hematopoietic cell lines transformed by BCR/ABL. In addition to p210BCR/ABL and c-ABL, p120CBL coprecipitated with an 85 kDa phosphoprotein, which was identified as the p85 subunit of PI3K. Anti-p120CBL immunoprecipitates from BCR/ABL-transformed, but not from untransformed, cell lines contained PI3K lipid kinase activity. Interestingly, the adaptor proteins CRKL and c-CRK were also found in these complexes. In vitro binding studies indicated that the SH2 domains of CRKL and c-CRK bound directly to p120CBL, while the SH3 domains of c-CRK and CRKL bound to BCR/ABL and c-ABL. The N-terminal and the C-terminal SH2 and the SH3 domain of p85PI3K bound directly in vitro to p120CBL. The ABL-SH2, but not ABL-SH3, could also bind to p120CBL. These data suggest that BCR/ABL may induce the formation of multimeric complexes of signaling proteins which include p120CBL, PI3K, c-CRK or CRKL, c-ABL and BCR/ABL itself.
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PMID:The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3' kinase pathway. 863 6

Characteristic of Philadelphia (Ph)+ chronic myelogenous leukemia (CML) is the presence of the chimeric BCR/ABL (p210) protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our previous studies demonstrated subtle differences in the growth, phenotypic and morphologic characteristics of the most primitive subpopulations of primary lin-Ph+ chronic phase CML blasts and comparable primary lin- normal blasts. Recently, in comparing proteins phosphorylated on tyrosine in these cell populations, we reported a prominent 62 kDa phosphotyrosyl (P-tyr) protein constitutively present in primary primitive lin- CML chronic phase blasts which was virtually undetectable in primary primitive lin- normal blasts. In the present studies, we demonstrate that this P-tyr p62 from primary primitive lin- chronic phase CML blasts co-immunoprecipitates with ras-GAP. Furthermore, in addition to the p210 protein, we show in whole cell lysates the presence of other clearly consistent but less prominent P-tyr proteins with molecular weights of approximately 155, 140, 110, 55 and 45 kDa as well as more minor P-tyr proteins of approximately 190, 85, 52, 42 and 39 kDa constitutively present in primary primitive lin- chronic phase CML blasts. In analyzing proteins tyrosine phosphorylated in primary primitive lin- normal blasts in response to various hematopoietic growth factors, we found a striking similarity in the phosphorylation of four major (approximately 140, 110, 62 and 56 kDa) and three minor (approximately 51, 45 and 42 kDa) P-tyr proteins after stimulation with c-kit ligand and the P-tyr proteins constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other growth factors tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand and EPO) were much less active or stimulated phosphorylation of other proteins. It is provocative that at least seven proteins rapidly and transiently phosphorylated on tyrosine in the c-kit ligand signal transduction pathway in lin- normal blasts may be constitutive substrates for the p210 activated tyrosine kinase in comparable lin- chronic phase CML blasts. In addition, it is intriguing that some of the biological effects on hematopoietic progenitors attributed to the c-kit ligand may be similar to some of the observed biological consequences of the p210 protein, including survival and expansion of a more mature stem cell population, probably at the time of lineage commitment rather than at the level of the earliest self-renewing stem cell.
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PMID:c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia. 863 31

We have previously reported that selection of marrow cells on the basis of the CD34+HLA-DR- phenotype (34+DR-) may result in the recovery of Philadelphia chromosome (Ph)- and BCR/ABL-negative long-term culture-initiating cells (LTC-IC) in selected patients with chronic myelogenous leukemia (CML). We now present data on 27 early chronic-phase ([ECP] studied within 1 year after diagnosis) and 23 advanced-phase ([AP] late chronic phase, ie, studied >1 year from diagnosis, or accelerated phase) CML patients. Fluorescence-activated call-sorting (FACS)-selected 34+DR- and 34+DR+ cells were subjected to reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization. These cells were also cultured in long-term bone marrow culture for 1 to 5 weeks to examine the number of LTC-IC and the presence or absence of the BCR/ABL gene rearrangement in progeny of primitive LTC-IC. The number of 34+DR- cells and LTC-IC present in ECP CML marrow was similar to that in normal (NL) marrow, whereas the numbers were reduced in AP CML. Furthermore, 34+DR- cells from more than 80% of ECP CML patients were BCR/ABL mRNA- and Ph-negative and contained only BCR/ABL mRNA- and Ph-negative LTC-IC, whereas 34+DR- cells and LTC-IC from less than 40% of AP CML patients were BCR/ABL mRNA- and Ph-negative. In contrast to NL marrow, 34+DR+ cells from CML marrow, irrespective of clinical stage, contained large numbers of LTC-IC. CML 34+DR+ cells and LTC-IC were BCR/ABL mRNA- and Ph-positive. Since these studies suggested that a population of primitive progenitors that are Ph-negative can be selected from steady-state marrow in some ECP CML patients, we determined if similar results could be obtained when large quantities of marrow sufficient for transplantation are processed. We demonstrate that 1 to 3 x 10(5) BCR/ABL mRNA-negative 34+DR- cells/kg recipient body weight, containing only BCR/ABL mRNA-negative LTC-IC, can be obtained from a 2- to 2.5-L marrow collection by sequential COBE Spectra apheresis (COBE BCT, Lakewood, CO), CD34+ enrichment using the CEPRATE SC Cell-Concentrator (CellPro, Bothell, WA), and high-speed FACS. Thus, large-scale selection of a BCR/ABL mRNA- and Ph-negative 34+DR- cell population is possible in a fraction of chronic-phase CML patients, in whom these cells could be used to reconstitute the hematopoietic compartment following autologous transplantation.
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PMID:BCR/ABL-negative primitive progenitors suitable for transplantation can be selected from the marrow of most early-chronic phase but not accelerated-phase chronic myelogenous leukemia patients. 863 48

Fluorescence in situ hybridization (FISH) and cytogenetic analysis were carried out in 33 transplanted patients suffering from different hematologic disease using probes for X and Y chromosomes and ABL and BCR genes. FISH showed that recipient cells were invariably present during post-transplant follow-up. Stable minimal residual disease was associated with clinical and hematologic remission, while a progressive increase of host cells was strictly related with disease relapse. Cytogenetic investigation on the same samples showed recipient cells only in few cases. It was concluded that FISH analysis is useful for: (1) characterizing cases in which standard cytogenetic analysis has failed; (2) detecting host cells in sex-mismatched transplanted patients; and (3) evaluating Ph-negative CML with the BCR/ABL rearrangement. The possibility of detecting chromosome rearrangements in interphase nuclei using FISH analysis improves diagnosis and prediction of disease evolution and prompts earlier therapeutic approaches.
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PMID:FISH detection of mixed chimerism in 33 patients submitted to bone marrow transplantation. 864 Jan 72

Among 84 consecutive patients with chronic phase Ph-positive chronic myeloid leukemia (CML) who were investigated for the hybrid BCR/ABL mRNA, in six cases (7%) the disease mimicked essential thrombocythemia (ET) at presentation, because of marked thrombocytosis (platelet counts ranging from 1003 x 10(9)/l to 2800 x 10(9)/l) and moderate leukocytosis (WBC counts from 10 x 10(9)/l to 19 x 10(9)/l). At initial examination, four of the six patients showed a few (4-9%) immature myeloid cells in the peripheral blood, and two had blood basophilia. All six patients later developed increasing leukocytosis, and two subsequently died from blast crisis and accelerated CML, respectively. In the overall series, 38 patients (45%) expressed the b2a2 type of BCR/ABL mRNA, and 46 (55%) either the b3a2 or both mRNAs. By contrast, only one of the six patients with CML of thrombocythemic onset expressed the b2a2 mRNA vs five with either b3a2 (n = 4) or both mRNA types (n = 1). The above results, in conjunction with similar data from a few previously published cases, suggest an association between the above form of CML and b3a2 type of BCR/ABL transcript.
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PMID:Chronic myeloid leukemia of thrombocythemic onset: a CML subtype with distinct hematological and molecular features? 909 6

We investigated a patient with Philadelphia chromosome (Ph) negative but BCR positive chronic myeloid leukemia (CML) by fluorescence in situ hybridization (FISH). In the chronic phase one chromosome 9 contained a BCR/ABL fusion gene instead of chromosome 22. Although in blast crisis, both chromosomes 9 had BCR/ABL fusion genes. This could be caused by duplication of the rearranged chromosome 9, which may have a significance similar to a double Ph chromosome. This may suggest that the critical event in CML is the formation of a BCR/ABL chimeric gene regardless of its locus in the genome.
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PMID:Duplication of chromosome 9 carrying a BCR/ABL chimeric gene in Philadelphia chromosome negative chronic myeloid leukemia. 869 26

Chronic myelogenous leukemia is a clonal proliferative disorder of pluripotent hematopoietic stem cells. Cure may be achieved by myeloablative conditioning treatment and marrow transplantation. In addition, allogeneic marrow can exert a graft-versus-leukemia effect. The graft-versus-leukemia effect may be directed against leukemia-specific antigens or against antigens on all hematopoietic cells, or it can be part of a graft-versus-host reaction. We report an informative post-transplant course of a patient with yet another leukemia-specific effect. This patient was transplanted with marrow from his HLA-identical sister in an advanced phase of CML and developed acute and chronic GVHD. After a severe pneumonia a high proportion of his metaphases in the bone marrow were male and Philadelphia chromosome negative. Later all metaphases were again female and leukemic cells could not be detected by reverse transcriptase polymerase chain reaction analysis (RT-PCR) for BCR/ABL. This course indicates that normal hematopoietic stem cells may survive intensive chemotherapy, bone marrow transplantation and GVHD. They may be recruited from a dormant state into proliferation during severe infections. In contrast, CML may be eliminated by the graft-versus-host reaction that recognizes recruited cells and spares dormant cells.
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PMID:Graft-versus-host reaction spares normal stem cells in chronic myelogenous leukemia. 870 5

A 48-year-old male was diagnosed to be unclassified chronic myeloproliferative disorder (UCMPD)/Ph negative bcr rearrangement negative (Ph-/bcr-) CML by hematological, cytogenetical and DNA analyses (Jpn. J. Clin. Hematol. 33(4): 525-531, 1992). Three years and a half after the diagnosis of UCMPD/Ph-bcr- CML, Ph chromosome was observed in 17 of 20 examined cells. Hematological findings showed a transformation into blast crisis. The late appearing of Ph in a case of UCMPD/Ph1-bcr- CML described here is rare. Southern blot analysis using 3' and 5' bcr probe showed no bcr rearrangement. Analyses of BCR/ABL chimeric RNA by RT-PCR method were negative in both of Major- and Minor BCR/ABL chimeric RNA. In the present case it is speculated that Ph is developed as the result of multistep progression and also speculated that the breakpoint at BCR gene differs from Major- and Minor-bcr in usual Ph+CML and de nove Ph+ ALL. Therefore, it may be reasonable that the present case is understood to be a case with late appearing Ph-like chromosome.
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PMID:[Unclassified chronic myeloproliferative disorder (Ph negative/bcr rearrangement negative CML) with late appearing Philadelphia like chromosome]. 872 46


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