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)

Advances in the molecular characterization of leukemic cells have greatly improved the precision of diagnosis and treatment assignment as well as the monitoring of residual disease in both acute lymphoblastic leukemia and acute myeloid leukemia. Currently, specific genetic rearrangements can be identified in as many as 50% of children with either acute lymphoblastic leukemia or acute myeloid leukemia. The genes p16 (or MTS1) and TEL/AML1 are now respectively recognized as the most common tumor suppressor and fusion genes in childhood acute lymphoblastic leukemia. Increasingly, contemporary protocols for the acute leukemias are relying on genetic information to guide treatment decisions. Examples include the use of allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with the BCR-ABL fusion gene or MLL rearrangement, and for acute myeloid leukemia with monosomy 7; antimetabolite-based therapy for acute lymphoblastic leukemia cases with hyperdiploidy of more than 50 chromosomes (DNA index > or = 1.16); and retinoic acid and anthracycline-containing regimens for the acute promyelocytic acute myeloid leukemia subtype with PML-RARA fusion. Other efforts are being made to reduce the long-term sequelae of treatment. Indeed, extended intrathecal therapy and intensive systemic chemotherapy will, in all likelihood, replace cranial irradiation as subclinical central nervous system therapy for patients with intermediate-risk acute lymphoblastic leukemia, and perhaps even for those with high-risk acute lymphoblastic leukemia. The challenge now is to identify specific treatments for other genetically defined subtypes of leukemia. This goal will be realized only through protocol-based studies employing uniform criteria for defining risk status.
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PMID:Acute leukemia in children. 937 85

After treatment of acute leukemia (typically ALL and the monocytic variants of AML), relapse may occur at sites other than the marrow. Isolated extramedullary relapse of acute promyelocytic leukemia (APL) however, is rare. We describe such an event in a man who underwent allogeneic BMT for APL in second relapse and 4 years later presented with testicular relapse. The marrow was morphologically and cytogenetically normal, but RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript.
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PMID:Testicular relapse of acute promyelocytic leukemia after allogeneic BMT. 1021 58

Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.
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PMID:Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. 938 4

Acute promyelocytic leukaemia (APL) is characterized cytogenetically by t(15;17)(q22:q21) which results in the production of a PML/RAR alpha fusion protein. Detection of the translocation or the fusion gene product is required for objective diagnosis of APL. This can be accomplished by conventional cytogenetic methods, fluorescence in situ hybridization or RT-PCR. Such techniques are time consuming and not universally available. The intracellular distribution of the PML protein in promyelocytes is characteristically altered in APL and this can be detected by immunocytochemistry. We have assessed two immunocytochemical methods, immunofluorescence and alkaline phosphatase-anti-alkaline phosphatase staining (APAAP), with regard to sensitivity, specificity and rapidity of diagnosis. 85 patients with AML including 15 cases of APL were studied. Immunofluorescence PML detection was concordant with RT-PCR for t(15:17) in 14/15 (93.3%) cases with no false positives. The negative APL case in our series was a patient with a 5' PML breakpoint who did not express the reciprocal t(17;15) fusion product. APAAP was concordant in only 6/13 (46%) APL cases with one false positive. In conclusion, immunofluorescent localization of PML using 5E10 monoclonal antibody is a rapid, sensitive and specific diagnostic tool for APL.
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PMID:The rapid diagnosis of acute promyelocytic leukaemia using PML (5E10) monoclonal antibody. 940 Oct 72

We investigated the effect of the acute promyelocytic leukemia (APL) specific PML/RARalpha fusion protein on the sensitivity to TNF-alpha-mediated apoptosis. The U937 leukemia cell line was transduced with PML/RARalpha cDNA. PML/RARalpha expression caused a markedly reduced sensitivity to TNF-alpha, even if apoptosis was triggered by agonistic antibodies to TNF-alpha receptors I and II (TNF-alphaRI, II). PML/RARalpha induced a 10-20-fold decrease of the TNF-alpha-binding capacity via downmodulation of both TNF-alphaRI and TNF-alphaRII: this may mediate at least in part the reduced sensitivity to TNF-alpha. Furthermore, the fusion protein did not modify Fas expression (CD95) or sensitivity to Fas-mediated apoptosis. The pathophysiological significance of these findings is supported by two series of observations. (a) Fresh APL blasts exhibit no TNF-alpha binding and are resistant to TNF-alpha-mediated apoptosis. Conversely, normal myeloblasts-promyelocytes show marked TNF-alphaR expression and are moderately sensitive to TNF-alpha-mediated cytotoxicity. Similarly, blasts from other types of acute myeloid leukemia (AML M1, M2, and M4 FAB types) show an elevated TNF-alpha binding. (b) The NB4 APL cell line, which is PML/RARalpha+, shows low TNF-alphaR expression capacity and is resistant to TNF-alpha-triggered apoptosis; conversely a PML/RARalpha- NB4 subclone (NB4.306) exhibits detectable TNF-alpha-binding capacity and is sensitive to TNF-alpha-mediated cytotoxicity. These studies indicate that the PML/RARalpha fusion protein protects against TNF-alpha-induced apoptosis, at least in part via downmodulation of TNF-alphaRI/II: this phenomenon may play a significant role in APL, which is characterized by prolonged survival of leukemic blasts.
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PMID:The PML/RARalpha fusion protein inhibits tumor necrosis factor-alpha-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts. 959 84

The development of therapy-related acute myeloid leukemia (t-AML) has become a growing concern over the past decade, because of the increase in the percentage of long-term survivors of primary malignancy. We reviewed 17 cases with etoposide-related acute promyelocytic leukemia (APL) reported in the literature. The close association between treatment with etoposide for Langerhans cell histiocytosis (LCH) and the development of etoposide-related APL was demonstrated among Japanese and Italians. Our data on the breakpoints (b/ps) of the PML and RARalpha genes are presented. It is suggested that chromatin structure might be more important than specific consensus sequence in the distribution of b/ps in etoposide-related APL.
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PMID:Etoposide-related acute promyelocytic leukemia. 969 69

Fluorescent in situ hybridization (FISH) is a rapid, sensitive and reliable method for the identification of complete chromosomes, or segments of them, during metaphase or nuclear interphase. The present study shows the results of the analysis of 32 bone marrow aspirates from patients with malignant hematological diseases (11 AML, 7 ALL, 12 CML and 2 CLL), referred to the Medical Genetics Unit of the Faculty of Medicine, Zulia University, Maracaibo, Venezuela between 1994 and 1996. All samples were studied by conventional and molecular techniques (FISH), using probes of total chromosomes, alpha-satellites and locus specific. In patients with AML and ALL and FISH technique detected clonal chromosomal abnormalities, that were not found by the conventional cytogenetic technique. Furthermore, the PML-alpha RARA complex was identified in the promyelocytic acute leukemias. The presence of the molecular complex ABL-BCR was also demonstrated in CML. The present study demonstrates the usefulness of the FISH technique in the detection of clonal chromosomal abnormalities, which are important when considering the clinical care of patients with these pathologies.
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PMID:[Clonal chromosome abnormalities in malignant hematological diseases using fluorescence in situ hybridization]. 970 20

We investigated parental origin of rearranged chromosomes 9 and 22 (9q + and 22q -) in five patients with Ph-positive chronic myeloid leukemia (CML) using the C-banding and silver-staining methods of nucleolus organizer regions, respectively; of rearranged chromosome 21 (21q +) in seven patients with t(8;21)-positive acute myeloid leukemia (AML); and of rearranged chromosome 15 (15q +) in six patients with t(15;17)-positive AML. It was found that these rearranged chromosomes can be of either paternal or maternal origin. Although the number of patients examined was small, these results indicate that the genes rearranged as a result of these chromosome translocations (ABL, BCR, AML-1 and PML) are not genomically imprinted.
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PMID:No parental origin bias for the rearranged chromosomes in myeloid leukemias associated with t(9;22), t(8;21) and t(15;17). 971 10

Acute myeloid leukemia (AML) is still associated with a mortality of 60 to 80%. AML is characterized by a block in myeloid differentiation. The transcription factors PU.1 and C/EBPalpha are responsible for normal myeloid differentiation from stem cells to monocytes or granulocytes. In particular, PU.1 induces expression of the macrophage colony-stimulating factor (M-CSF) receptor and the development of monocytes, whereas C/EBPalpha increases the expression of the granulocyte colony-stimulating factor (G-CSF) receptor and leads to mature granulocytes. In AML, chromosomal aberrations result in oncoproteins such as AML1/ETO, PML/RARalpha, or activated Ras, which can deregulate genes important for normal myelopoiesis. Thus, AML1/ETO can bind to the transcription factor C/EBPalpha, inhibit C/EBPalpha-dependent transcription, and block granulocytic differentiation. However, AML1/ETO can also synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter. On the other hand, the PML/RARalpha fusion protein causes transcriptional repression by recruiting the nuclear corepressor (N-CoR) histone deacetylase complex to the DNA, which results in decreased histone acetylation and a repressive chromatin organization. Here we describe methods to investigate whether and how signaling agonists induce myeloid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid development.
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PMID:Analysis of the modulation of transcriptional activity in myelopoiesis and leukemogenesis. 1008 Sep 8

We report a case of acute myeloid leukemia FAB-type 2 with a translocation t(15;17)(q22;q12) On the basis of the cytological findings, a translocation t(8;21)(q22;q22) was suspected. FISH analyses using specific probes for t(15;17) and t(8;21) detected both PML/RARalpha and AML1/ETO rearrangements in a few percentage of cells. This case demonstrates the complexities that may occur between cytology and cytogenetic findings and the usefulness of FISH methods to detect an AML1/ETO rearrangement only suspected by cytological examination of bone marrow smears.
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PMID:Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17). 1022 24


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