UMLS:C0598766 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0598766 (leukemogenesis)
4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been supposed in de novo AML that malignant transformation occurs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regularly occur at the level of stem cells. These cells can be discriminated by function and specific surface molecules. CD34, a glycophosphoprotein, is a cellular surface antigen characteristically expressed by stem cells. CD34+ stem cells can be further subdivided by the expression of additional surface molecules like CD38 and CD117. In this article we present results from cytogenetic examinations of FACS-isolated stem cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalities; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the receptor for the stem cell factor (also KIT oncogene) as a new cellular surface marker. CD34+/CD117+/- stem cell subpopulations were examined in two patients with AML and three patients with MDS. We found leukemic stem cells in every type of stem cell subpopulation examined (CD34+/CD38-, CD34+/CD38+, CD34+/CD117-, CD34+/CD117+). Secondary, progression-associated chromosome abnormalities likewise were demonstrable in CD34+ cells. In three patients a mosaic of normal and abnormal metaphases was found in the highly purified stem cell subpopulations. We conclude that in AML and MDS stem cells are the target of leukemogenic genetic defects. CD117 as a new marker to isolate different CD34+ subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for autologous stem cell transplantation, high-dose chemotherapy and the pathogenetic concept of leukemogenesis.
...
PMID:Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117. 918 Feb 91

As recurrent chromosome abnormalities in leukemia are highly associated with particular subtypes, the genetic events of specific chromosome alteration must be associated with leukemogenesis and characteristics of the disease. The chromosomal breakpoints involved in inv(16) and t(16;16) have been shown to generate the fusion gene PEBP2beta(CBFbeta)/MYH11. The PEBP2beta/MYH11 fusion transcripts in all 8 patients with M4Eo, 2 of 18 with M4, and one CML in the blastic phase were detected by using RT-PCR and Southern blotting. We demonstrated the marked expression of CD34 and c-KIT (CD117) antigens in myelomonoblastic leukemia cells from all patients carrying this fusion gene, which was in contrast to the patients with M4 but without the fusion gene. These results indicate that immunophenotypic analysis is useful for detection of leukemia with the fusion gene, and that the PEBP2beta/MYH11 fusion gene is involved in immature cells expressing CD34 and c-KIT antigens.
...
PMID:Acute myelomonoblastic leukemia carrying the PEBP2beta/MYH11 fusion gene. 972 Jul 17

Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
...
PMID:Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. 1449 2

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.
...
PMID:Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. 1468 12

The Kasumi-1 cell line is an intensively investigated model system of Acute Myeloid Leukemia with t(8;21) translocation, that represents 1 of the 2 main subtypes of Core Binding Factor Leukemia (CBFL). Since establishment in 1991 the Kasumi-1 cell line has provided the tool to study the peculiar molecular, morphologic, immunophenotypic findings of AML with t(8;21) and the functional consequences of the AML1-ETO fusion oncogene on myeloid differentiation. Leukemogenesis involves multiple genetic changes and, as suggested by murine experiments and other findings in humans, AML1-ETO expression may not be sufficient for full blown leukemia. In agreement with the "two hits" model of leukemogenesis, based on the cooperation between 1 class of mutations that impair hematopoietic differentiation and a second class of mutations that confer a proliferative and/or survival advantage to hematopoietic progenitors an activating mutation in the tyrosine kinase domain of the c-kit gene was identified in the AML1/ETO expressing Kasumi-1 cell line. The dosage of the Asn822Lys mutated allele was shown to be about 5-fold compared to the normal allele and c-kit amplification was found to map to minute 4cen-q11 marker chromosomes, likely derived from the extra chromosome 4 recorded in the newly established cell line. The combination of t(8;21) and trisomy 4 leading to enhanced dosage of a mutated kit allele is a feature of a few CBFL patients reproduced by the Kasumi-1 cell model. The Kasumi-1 cell line, paralleling the commitment stage of CBF leukemia also provides a valuable resource to investigate the effect of tyrosine kinase kit mutant on the main KIT-regulated signal transduction pathways, i.e. MAPK, PI3K/AKT and STAT3 and the diverse inhibitory effect exerted by STI 571 on these KIT mutant activated pathways. PI3K-dependent activation of AKT and STAT activation was observed in Kasumi-1 cells. Contrary to the expectations for an amplified tyrosine kinase kit mutant, we found that STI 571 inhibited KIT Asn822Lys tyrosine phosphorylation and downstream JNK and STAT3 effectors in Kasumi-1 cells, but had no effect on constitutive activation of AKT, suggesting that signaling by tyrosine kinases other than KIT may be responsible for its activation in Kasumi-1 cells. Independent findings on the same model system provide complementary insights into designing strategies for treatment of CBF leukemia associated with mutations in the KIT catalytic domain.
...
PMID:The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. 1562 9

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.
...
PMID:AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. 1565 49

The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias.
...
PMID:The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. 1602 55

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.
...
PMID:Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. 1628 Oct 72

AML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in acute myeloid leukemia (AML) M0, myeloid malignancies with acquired trisomy 21, and certain myelodysplastic syndrome (MDS) cases. By correlating the presence of RUNX1 mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (N = 90) at diagnosis, we detected RUNX1 mutations in 46% of cases, with all trisomy 13 cases (n = 18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3 mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1 mutations (80%) was detected in cases with trisomy 13 from other French-American-British (FAB) subgroups (n = 20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1 mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3 transcript levels. Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3 overexpression might be a mechanism for FLT3 activation, which cooperates with RUNX1 mutations in leukemogenesis.
...
PMID:Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. 1748 49

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
...
PMID:Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. 1749 58

1 2 3 4 Next >>