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

The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic response (CCR) after Imatinib treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR/ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR/ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome.
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PMID:Molecular analysis of the Imatinib-induced complete cytogenetic response in chronic myelogenous leukemia. 1692 67

We describe here the first case of acute lymphoblastic leukemia (ALL) with an isodicentric Philadelphia [idic(Ph)] chromosome. A 35-year-old man was diagnosed as ALL because of the infiltration of CD10(+)CD19(+)CD33(+)CD34(+) lymphoblasts in the bone marrow and the expression of p190-type BCR/ABL fusion transcript. Chromosome analysis showed 45,XY,der(7;12)(q10;q10),der(9)t(9;22)(q34;q11),idic der(22)t(9;22)(q34;q11). The idic(Ph) chromosome was spindle-shaped and supposed to be formed by two Ph chromosomes joined at their q terminals, whereas idic(Ph) chromosomes in chronic myelogenous leukemia (CML) have been shown to be fused at the satellite regions of p arms. The results indicate that the structure of idic(Ph) chromosomes appears to be different between ALL and CML. The patient did not respond to any chemotherapy and could not achieve remission. This chromosome aberration in ALL may suggest poor prognosis as observed in some cases of CML. Furthermore, considering other three reported cases, der(7;12)(q10;q10) may be one of the recurrent translocations in ALL.
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PMID:Isodicentric Philadelphia chromosome in acute lymphoblastic leukemia with der(7;12)(q10;q10). 1697 35

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/ABL)(T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.
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PMID:FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. 1771 97

The chimeric oncogene Bcr-Abl is known to induce autonomous motility of leukemic cells. We show here that p210(bcr-abl) responsible for chronic myelogenous leukemia induces an amoeboid type of motility while p190(bcr-abl), associated with acute lymphoid leukemia, induces a rolling type of motility. We previously reported that p210(bcr-abl) activates RhoA and Rac1, while p190(bcr-abl) although devoid of a Dbl-homology (DH) domain activates Rac1, but not RhoA. We investigated the regulation of GDP/GTP exchange factor (GEF) activities in the Bcr-Abl complex. For that purpose, different GEF activity mutants of Vav and of Bcr-Abl were constructed and stably transfected in Ba/F3 cells. Using these mutants, we demonstrate that RhoA is exclusively activated by the DH domain of p210(bcr-abl), while Rac1 activation is mostly due to Vav. Inhibition of Rac1 by Vav GEF mutant leads to immobilization of cells. Vav depletion using shRNA also induces immobilization of cells and suppression of GTP-bound Rac1. RhoA inactivation induces the specific loss of amoeboid movements. These results suggest that Rac1 activation by Vav triggers the motility of Bcr-Abl-expressing Ba/F3 cells, while the specific amoeboid mode of motility induced by p210(bcr-abl) is a consequence of RhoA activation.
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PMID:Differential motility of p190bcr-abl- and p210bcr-abl-expressing cells: respective roles of Vav and Bcr-Abl GEFs. 1805 43

INK4A/ARF mutations are acquired in bcr/abl(+) lymphoid blast phase chronic myelogenous leukemia (CML) and bcr/abl(+) acute lymphoblastic leukemia (ALL). Donor lymphocyte infusion and graft-versus-leukemia (GVL) are generally ineffective in such ALLs, whereas GVL is highly active against bcr/abl(+) CML, which does not have a lesion in the INK4A/ARF locus. The mechanisms for the ineffectiveness of GVL are not fully known, and it is possible that intrinsic resistance of acute lymphoid leukemias to immune effectors associated with allogeneic GVL may contribute to ineffectiveness. This work tested the hypothesis that INK4A/ARF mutations that are associated with transformation of bcr/abl(+) CML to an ALL phenotype, and that are associated with increased resistance to apoptosis render ALL cells insensitive to allogeneic immune responses to minor histocompatibility antigens (mHA). Murine acute pre-B ALLs were induced by transfer of the human p210 bcr/abl gene into bone marrow of INK4A/ARF null mice. These ALL lines were then studied in a murine model of MHC-matched, mHA-mismatched allogeneic BMT. In vivo growth of these ALLs was inhibited in allogeneic transplants characterized by active allogeneic immune responses compared to their behavior in syngeneic transplants. In vitro ALLs with INK4A/ARF, p210 bcr/abl, or p190 bcr/abl mutations remained sensitive to anti-mHA cytolytic T cells. In addition, the ALLs were capable of inducing primary immune responses to mHAs in vivo. Thus, ALLs with INK4A/ARF or bcr/abl mutations are not intrinsically resistant to allogeneic T cell responses, suggesting that active immunotherapies against mHA have the potential to control such acute lymphoblastic leukemias.
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PMID:High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells. 1848 87

Chronic myeloid leukemia (CML) is a rare disease in childhood which is almost exclusively associated with bcr-abl p210 (M-bcr) rearrangements. It has been suggested that co-expression of p190 and p210 may be a pathway of CML progression in adult patients. We report two cases of pediatric patients with a diagnosis of CML who presented co-expression of the p210 and p190 transcripts during progression to the blastic phase. The present data suggest that p190 may be a secondary event in at least some cases of childhood CML, suggesting an association with progression to a blastic crisis in these patients.
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PMID:Is p190 bcr-abl rearrangement necessary for acute transformation in some p210 CML of childhood? 1849 45

It remains unresolved how different BCR-ABL transcripts differentially drive lymphoid and myeloid proliferation in Philadelphia chromosome-positive (Ph(+)) leukemias. We compared BCR-ABL transcript type and level with kinase domain (KD) mutation status, genotype, and phenotype in 1855 Ph(+) leukemias. Compared with e1a2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph(+) lymphoid leukemia more frequently showed CML-type background, had higher blast-normalized BCR-ABL transcript levels, and more frequent persistent BCR-ABL transcript in the absence of detectable lymphoblasts. Secondary lymphoid blast transformation of CML was exclusively due to e13/e14a2/p210 BCR-ABL but was associated, at a much higher level than p210 myeloid transformation, with acquisition of new KD mutations and/or Ph genomic amplification. In contrast, myeloid blast transformation was more frequently accompanied by new acquisition of acute myeloid leukemia-type chromosomal aberrations, particularly involving the EVI1 and RUNX1 loci. Therefore, higher kinase activity by mutation, transcriptional up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.
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PMID:BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias. 1880 62

The Bcr/Abl oncogene is responsible for the development of Ph-chromosome positive acute lymphoblastic leukemia and chronic myelogenous leukemia in humans. Previous studies demonstrated that Bcr/Abl expression is associated with elevated levels of activated Rap1, a small GTPase. Levels of activated Rap1 are determined by a balance between GTPase activating and G-nucleotide exchange factor activity. We show that Bcr/Abl forms a protein-protein complex with Spa-1, a GTPase activating protein for Rap1, both in COS-1 cells as well as in primary lymphoblastic leukemia cells from a transgenic P190 BCR/ABL mouse model. The interaction between Spa-1 and P190 did not affect the tyrosine kinase activity of P190, nor did Spa-1 become phosphorylated on tyrosine as a result of the interaction. P190 and Spa-1 co-localized to peripheral actin structures in primary lymphoblasts and expression of Spa-1 in the leukemic lymphoblasts decreased the migration of these cells. The binding of Bcr/Abl to Spa-1 may cause aberrant subcellular location of Spa-1 and affect migration of these cells.
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PMID:Bcr/Abl P190 interaction with Spa-1, a GTPase activating protein for the small GTPase Rap1. 1881 51

The Philadelphia (Ph) chromosome is characteristic of chronic myelogenous leukemia (CML), but it is also the most frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (ALL) of adults. The vast majority of CML patients have a BCR-ABL translocation that yields a 210 kD (p210) oncoprotein, whereas adult Ph-positive ALL cases can present with either a p190 or a p210 oncoprotein, or both. Considering that 30% of the patients with CML that progress to blast crisis will have a lymphoblastic presentation, adults presenting with a p210 ALL may have either a de novo ALL or CML presenting for the first time in lymphoblastic phase. To identify the distinguishing features, cases of p190-ALL, p210-ALL, and lymphoblastic CML were compared. In spite of significant overlap between the three entities, a number of features were found to aid in their differentiation. p210-ALL patients present at a younger age with blasts that frequently show loss of expression of CD34, whereas p190-ALL patients present with marked increase in peripheral blast percentage. Interestingly, bone marrow findings characteristic of a myeloproliferative disorder are specific, but are not sensitive for lymphoblastic CML. This study suggests that despite the similarities between these leukemias, p190-ALL, p210-ALL, and lymphoblastic phase CML likely represent three distinct diseases.
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PMID:The spectrum of adult B-lymphoid leukemias with BCR-ABL: molecular diagnostic, cytogenetic, and clinical laboratory perspectives. 1893 38

An atypical case of Philadelphia (Ph) negative, e1a2 BCR-ABL transcript positive chronic myeloid leukemia (CML) characterized with cyclic periodic leukocytosis and spontaneous remissions is reported. The patient was treated with imatinib and good hematology response with molecular remission was achieved. So far, only few Ph positive CML patients expressing p190 BCR-ABL protein and different clinical characteristics and treatment have been described in the literature. This is the first report of Philadelphia negative, p190 BCR-ABL positive CML with cyclic spontaneous oscillation of white blood cell count (WBC), and excellent response to imatinib treatment.
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PMID:Molecular response to imatinib in patient with Ph negative p190 BCR-ABL transcript positive chronic myeloid leukemia with cyclic leukocytosis. 1909 3


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