Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TEL/ARG oncogene associated with acute myeloid leukemia is formed by the t(1;12)(q25;p13) reciprocal translocation, which fuses part of the TEL gene to the tyrosine kinase, c-ARG. In an effort to determine the biological effects and investigate signaling of the TEL/ARG fusion protein, multiple sublines of Ba/F3 cells were generated in which a TEL/ARG complementary DNA was expressed under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, rapidly induced expression of the TEL/ARG protein. TEL/ARG was heavily phosphorylated on tyrosine residues and was also found to rapidly induce tyrosine phosphorylation of multiple cellular proteins, including rasGAP, CBL, STAT5, PI3K, SHP2, Dok, and SHC. The Ba/F3-tet-TEL/ARG cells remained interleukin (IL)-3 dependent without doxycycline but with doxycycline displayed a marked reduction in cell death in the absence of IL-3. TEL/ ARG cells also displayed an enhanced proliferative response to IL-3 and to insulin-like growth factor 1. At least in Ba/F3 cells, although the growth rate was much lower compared to that with IL-3, TEL/ARG appeared to induce some cell proliferation as an immediate consequence. Nonetheless, the hyperresponsiveness to growth factors reported here is more likely to contribute to the pathogenesis of leukemia.
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PMID:The TEL/ARG leukemia oncogene promotes viability and hyperresponsiveness to hematopoietic growth factors. 1500 41

The human FHIT (fragile histidine triad) gene is a putative tumor suppressor gene located at chromosome region 3p14.2. Previous studies have shown that loss of heterozygosity, homozygous deletions, and abnormal expression of the FHIT gene are involved in several types of human malignancies. A CpG island is present in the 5' promoter region of the FHIT gene, and methylation in this region correlates with loss of FHIT expression. To test whether aberrant methylation of the FHIT gene may play a role in pediatric leukemia, we assessed the FHIT methylation status of 10 leukemia cell lines and 190 incident population-based cases of childhood acute lymphocytic and myeloid leukemias using methylation-specific PCR. Conventional and fluorescence in situ hybridization cytogenetic data were also collected to examine aneuploidy, t(12, 21), and other chromosomal rearrangements. Four of 10 leukemia cell lines (40%) and 52 of 190 (27.4%) bone marrows from childhood leukemia patients demonstrated hypermethylation of the promoter region of FHIT. Gene expression analyses and 5-aza-2'-deoxycytidine treatment showed that promoter hypermethylation correlated with FHIT inactivation. Among primary leukemias, hypermethylation of FHIT was strongly correlated with acute lymphoblastic leukemia (ALL) histology (P = 0.008), high hyperdiploid (P < 0.0001), and translocation-negative (P < 0.0001) categories. Hyperdiploid B-cell ALLs were 23-fold more likely to be FHIT methylated compared with B-cell ALL harboring TEL-AML translocations. FHIT methylation was associated with high WBC counts at diagnosis, a known prognostic indicator. These results suggest that hypermethylation of the promoter region CpG island of the FHIT gene is a common event and may play an important role in the etiology and pathophysiology of specific cytogenetic subtypes of childhood ALL.
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PMID:Hypermethylation of the 5' CpG island of the FHIT gene is associated with hyperdiploid and translocation-negative subtypes of pediatric leukemia. 1502 36

A total of 69 patients of B lineage ALL, 35 children (32 males, 3 females) and 34 young adults (27 males, 7 females) were studied by multiplex RT-PCR to determine the relative frequency of t(9;22), t(12;21), t(1;19), and t(4;11,). Translocation (9;22) was seen in 1/35 (2.8%) and t(1;19) in 2/35 (5.7%) children. None of the children showed t(12;21) and t(4;11) translocations. In young adults, t(9;22) and t(1;19) were seen in 5/34 (14.7%) and 2/34 (5.8%) patients, respectively. None of the latter showed t(12;21) or t(4;11) translocations. Thus, there appears to be a significant under representation of the fusion transcripts for TEL-AML, a good prognostic marker, in this study, unlike in the West, where it is seen in 35% of children with ALL. This, together with the generally increased leukemic burden seen in Indian patients, may explain in part, the poor treatment outcome reported.
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PMID:Paucity of TEL-AML 1 translocation, by multiplex RT-PCR, in B-lineage acute lymphoblastic leukemia (ALL) in Indian patients. 1511 4

We previously reported a novel fusion between TEL and FGFR3 in a patient with peripheral T-cell lymphoma with t(4; 12)(p16;p13). Disease in this patient subsequently progressed to acute myelogenous leukemia (AML) with the same translocation. Sequence analysis of TEL-FGFR3 fusion transcripts suggested that these diseases originated from the same multipotent stem cell. To determine the transforming property of TEL-FGFR3, we established transfectants of this chimeric fusion gene and investigated the major signal pathways of TEL-FGFR3-induced transformation using various signal transduction inhibitors including SU5402 (fibroblast growth factor tyrosine kinase [FGFR TK] inhibitor). Our results indicated that (1) the expression of TEL-FGFR3 but not DeltaHLH-TEL-FGFR3 resulted in efficient focus formation in NIH/3T3 cells and conferred interleukin 3 independence to Ba/F3 cells by a constitutive tyrosine kinase activity probably through oligomerization by the HLH domain of TEL; (2) although effector proteins including classical mitogen-activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3-kinase (PI3-K), mammalian target or rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT-3) and STAT-5 were activated in TEL-FGFR3 transformants, the growth of the transformants was inhibited by SU5402 (concentration that inhibits 50% [IC5)]=5 microM) and the PI3-K inhibitor, LY294002 (IC5)=10 microM) and wortmannin (IC50=5 microM), but not by U0126, SB203580, or rapamycin; and (3) injection of TEL-FGFR3 transformants induced lethal leukemia into syngeneic mice. Taken together, the leukemogenic potential of TEL-FGFR3 may be mediated in part through PI3-K.
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PMID:Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML. 1551 5

In about 55% of acute myeloid leukemia (AML) cases, chromosome aberrations are detectable by cytogenetics. Close correlations between cytomorphology and cytogenetics have been reported. To determine a pattern of cytogenetic abnormalities within the French-American-British (FAB) subtypes AML M0, M1, and M2, we analyzed 48 AML M0, 179 AML M1, and 425 AML M2 and compared cytogenetic data to a cohort of 1,062 AML M3/3v, M4, M4eo, M5a/5b, M6, and M7. Cytogenetic abnormalities were significantly more frequent in AML M0 (71%) compared to M1 (49%), M2 (53%), and the total cohort (56%; P < 0.02). While +8 was the most common numeric abnormality in all FAB subtypes, +13, +14, and +11 were associated with AML M0-M2. The only recurring balanced translocation that was associated with one of these FAB subtypes was t(8;21) in M2 (12.5%) and, rarely, M1 (1.7%) (M0, 0% and M3-7, 0.09%; P=0.001). To evaluate the frequency of cytogenetically undetectable abnormalities, we performed fluorescence in situ hybridization (FISH) analyses in 273 AML M0-M2 with normal karyotype using probes for ETO, ABL, MLL, TEL, RB, P53, AML1, and BCR. In two cases we identified numerical aberrations of RB only in interphases nuclei. In seven additional cases, TEL and MLL abnormalities were found. In conclusion, t(8;21), +11, +13, and +14 are strongly associated with AML M0, M1, and M2. The FISH screening analyses identified abnormalities in an additional 3% in normal karyotypes.
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PMID:Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization. 1552 2

Major strides have been made in our understanding of the molecular basis of adult and pediatric leukemias. More than one hundred disease alleles have been identified and characterized in cell culture and murine models of leukemia. In some instances, molecularly targeted therapies have been developed based on these insights that are currently in clinical trials, such as small molecule inhibitors of FLT3. In addition, it has recently been appreciated that, as with normal hematopoiesis, there is a hierarchical organization among leukemic cells that includes a rare population of leukemic stem cells that have properties of self-renewal. Understanding the characteristics of these leukemic stem cells may provide new insights into leukemia therapies that target self-renewal pathways. In Section I, Dr. Craig Jordan reviews the data that supports the existence of a "leukemia stem cell." He provides an overview of the functional properties of leukemic stem cells, their relationship to hematopoietic stem cells, and the relevance of leukemic stem cells in other human malignancies including solid tumors. He briefly discusses what is known of the pathways that regulate properties of self-renewal. Dr. Gary Gilliland provides an overview of the genetics of adult leukemias in Section II and ongoing genome-wide strategies for discovery of new disease alleles. He describes the clinical and therapeutic implications of these findings and provides examples of bench-to-bedside translation of molecularly targeted therapies for AML, including the use of FLT3 inhibitors. In Section III, Dr. Carolyn Felix reviews recent advances in our understanding of the genetics and therapy of pediatric leukemias. She provides an overview of leukemias that are common in pediatric malignancies but rarely observed in adults, including the TEL-AML1 (ETV6-RUNX1) fusion associated with pediatric B-cell ALL, the OTT-MAL fusion associated with infant megakaryoblastic leukemia, PTPN11 mutations in juvenile myelomonocytic leukemia, and MLL fusion genes in leukemogenesis, among others.
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PMID:The molecular basis of leukemia. 1556 78

After stem cell transplantation (SCT) close follow-up of chimerism and/or clonal disease markers is essential for early treatment of graft failure or relapse. We wanted to assess the sensitivity, clinical reliability and practicability of inter-phase FISH on untreated, native smears of BM or PB for this purpose. We investigated 23 children after SCT with sex mismatch (MM) and/or clone specific markers (monosomy 7, trisomy 8, MLL rearrangement, bcr-abl, TEL-AML-1). Diagnoses were ALL (8), AML (6), MDS (2), CML (2), large cell anaplastic lymphoma (1) and SAA (4). Eighteen children were transplanted from sex-mismatched donors, seven among them had shown a clonal marker at diagnosis. The remaining five patients with sex matched donors also had a clonal marker. For FISH, we used commercial probes on fresh or stored unmanipulated smears of PB or BM. Cut-off levels for clonal markers were established on control probands without hematologic disease, for host sex on probands of the opposite sex, respectively (mean +3 SD). The presence of host cells and/or clonal markers established at diagnosis by conventional karyotyping was followed up after SCT at regular intervals by FISH. Nineteen of the 23 patients studied achieved and maintained complete continuous hematologic remission with corresponding absence of host and/or disease markers. In one of them, a fatal extramedullary relapse occurred. The associated mixed chimerism was confirmed by FISH. In all four cases with hematological relapse, the respective marker (MLL, bcr-abl, Mo 7) reappeared and was successfully monitored during DLI and repeat SCT in two as well as parallelled by simultaneous demonstration of host cells in the two sex mismatched cases among them. We demonstrate the usefulness of FISH on native smears for clinical routine follow-up of SCT patients. FISH allowed identification of cell origin in non-hematologic material (spinal fluid, pericardial effusion). Chimerism analysis in BM was slightly more sensitive than in PB. FISH was feasible on frozen stored smears as well.
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PMID:FISH analysis of native smears from bone marrow and blood for the monitoring of chimerism and clonal markers after stem cell transplantation in children. 1564 46

ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization- or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.
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PMID:Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. 1580 61

Aberrant expression of tumor suppressor genes WT 1, RB 1, p53, homozygous deletion of p16 gene and their relationship with expression of oncogenes BCR-ABL, TEL-AML 1, MLL-AF 4, E2A-PBX 1, SIL-TAL 1 were determined in bone marrow samples of children with de novo B-lineage (n=170) and T-lineage (n=25) acute lymphoblastic leukemia (ALL). In contrast to expression of chimeric oncogenes alterations in p16, WT 1, RB 1 and p53 expression were T/B-lineage-unrestricted. Significant association between expression of MLL-AF 4 and WT 1, E2A-PBX 1 and p53; SIL-TAL 1 and homozygous deletion of p16 has been demonstrated.
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PMID:Aberrant expression of tumor suppressor genes and their association with chimeric oncogenes in pediatric acute lymphoblastic leukemia. 1587 20

Leukemia is the most common cancer to affect children, accounting for approximately a third of all childhood cancers. The major morphological subtypes of leukemia, acute lymphoblastic leukemia (ALL), and acute myeloblastic leukemia (AML), are characterized by chromosomal translocations involving over 200 genes including mixed lineage leukemia (MLL), TEL, and AML1. Chromosomal translocations involving the MLL gene at 11q23 are a common feature of infant acute leukemia, found in up to 80% of all cases, and there is strong evidence that rearrangements involving the MLL gene or the TEL-AML1 gene fusion can originate in utero. As with most other cancers, the mechanism by which leukemia arises is likely to involve gene-environment interactions. Accordingly, it is important to identify exposures that cause DNA damage and induce chromosome breaks which are inadequately repaired, ultimately leading to the initiation and disease progression. Exposures acting before birth and early in life has long been thought to be important determinants of leukemia, and the list of suspected chemical, physical, and biological agents continues to increase. Unfortunately, the evidence regarding the majority of suggested exposures is limited and often contradictory, and there are areas, which clearly warrant further investigation in order to further our understanding of the aetiology of childhood leukemia.
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PMID:Aetiology of childhood leukemia. 1605 22


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