Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in transcription factors (TFs) and protein tyrosine kinases (PTKs), which result in inhibition of differentiation/apoptosis or enhanced proliferative/survival advantage of hematopoietic stem/progenitor cells, are two classes of the most frequently detected genetic abnormalities in leukemias. The critical roles for mutant TFs and/or PTKs to play in leukemogenesis, and the absence of mutant TFs/PTKs in normal hematopoietic cells, suggest that the two types of aberrant molecules may serve as ideal therapeutic targets. The great success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia through modulation of the causative PML-RARalpha oncoprotein represents the first two paradigms of mutant TFs-targeting therapeutic strategies for leukemia. More recently, tyrosine kinase inhibitor STI-571/Imatinib mesylate/Gleevec in the treatment of Breakpoint Cluster Region-Abelson (BCR-ABL) positive leukemia elicits paradigm of mutant PTKs as ideal antileukemia targets. Thus to further improve clinical outcome of leukemia patients, elucidation of pathogenesis of leukemia, screening for oncoprotein-targeting small molecules, as well as rationally designed combination of drugs with potential synergy are of importance.
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PMID:Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias: from acute promyelocytic leukemia to chronic myeloid leukemia and beyond. 1743 11

Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitor cells that involves dynamic change in the genome. Dissection of genetic abnormalities critical to leukemia initiation provides insights into the elusive leukemogenesis, identifies distinct subsets of leukemia and predicts prognosis individually, and can also provide rational therapeutic targets for curative approaches. The past three decades have seen tremendous advances in the analysis of genotype-phenotype connection of leukemia, and in the identification of molecular biomarkers for leukemia subtypes. Intriguingly, differentiation therapy, targeted therapy and chemotherapy have turned several subtypes of leukemia from highly fatal to highly curable. The use of all-trans retinoic acid and arsenic trioxide, which trigger degradation of PML-RARalpha, the causative fusion protein generated by t (15;17) translocation in acute promyelocytic leukemia (APL), has led to a dramatic improvement of APL clinical outcome. Imatinib mesylate/ Gleevec/STI571, which inhibits the tyrosine kinase activity of BCR-ABL oncoprotein, has now become the new gold standard for the treatment of chronic myeloid leukemia. Optimal use of chemotherapeutic agents together with a stringent application of prognostic factors for risk-directed therapy in clinical trials has resulted in a steady improvement in the treatment outcome of acute lymphoblastic leukemia. Hence, the pace of progress extrapolates to a prediction of leukemia control in the twenty-first century.
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PMID:From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies: leukemia research in the genomic era. 1772 77

Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) is the most frequent RARalpha fusion protein in acute promyelocytic leukemia (APL). Our previous study has demonstrated that, compared with RARalpha, PML-RARalpha had reduced intranuclear mobility accompanied with mislocalization. To understand the molecular basis for the altered dynamics of PML-RARalpha fusion protein, we performed FRAP analysis at a single cell level. Results indicated that three known sumoylation site mutated PML-RARalpha had same intracellular localization and reduced mobility as wild-type counterpart. The coiled-coil domain of PML is responsible for the aberrant dynamics of PML-RARalpha. In addition, we revealed that co-repressor SMRT co-localized with PML-RARalpha, resulting in the immobilization of SMRT while ATRA treatment eliminated their association and reversed the immobile effect of SMRT. Furthermore, co-activator CBP, co-localized with PML-RARalpha in an ATRA-independent way, was demonstrated as a high dynamic intranuclear molecule. These results would shed new insights for the molecular mechanisms of PML-RARalpha-associated leukemogenesis.
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PMID:Coiled-coil domain of PML is essential for the aberrant dynamics of PML-RARalpha, resulting in sequestration and decreased mobility of SMRT. 1799 21

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARalpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARalpha-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL. RARalpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.
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PMID:RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. 1800 64

In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARbeta2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
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PMID:MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. 1864 63

PML, a nuclear protein, interacts with several transcription factors and their coactivators, such as HIPK2 and p300, resulting in the activation of transcription. Although PML is thought to achieve transcription activation by stabilizing the transcription factor complex, little is known about the underlying molecular mechanism. To clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. PML inhibited this degradation through a mechanism that unexpectedly did not involve inhibition of the ubiquitination of HIPK2. PML, Fbx3, and HIPK2 synergistically activated p53-induced transcription. Our findings suggest that PML stabilizes the transcription factor complex by protecting HIPK2 and p300 from SCF(Fbx3)-induced degradation until transcription is completed. In contrast, the leukemia-associated fusion PML-RARalpha induced the degradation of HIPK2. We discuss the roles of PML and PML-retinoic acid receptor alpha, as well as those of HIPK2 and p300 ubiquitination, in transcriptional regulation and leukemogenesis.
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PMID:PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation. 1880 79

Tumor suppressor genes, such as p53, RB, the INK4-ARF family and PML, suppress malignant transformation by regulating cell cycle progression, ensuring the fidelity of DNA replication and chromosomal segregation, or by inducing apoptosis in response to potentially deleterious events. In myeloid leukemia, hematopoietic differentiation resulting from highly coordinated, stage-wise expression of myeloid transcription and soluble signaling factors is disrupted leading to a block in terminal differentiation and uncontrolled proliferation. This virtually always involves functional inactivation or genetic disruption of one or several tumor suppressor genes in order to circumvent their checkpoint control and apoptosis-inducing functions. Hence, reactivation of tumor suppressor gene function has therapeutic potential and can possibly enhance conventional cytotoxic chemotherapy. In this review, we focus on the role of different tumor suppressor genes in myeloid differentiation and leukemogenesis, and discuss implications for therapy.
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PMID:Tumor suppressor genes in myeloid differentiation and leukemogenesis. 1928 82

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.
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PMID:Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells. 1929 93

Acute myeloid leukemia (AML) is caused by the cooperation between class I, mostly mutated receptor tyrosine kinases (RTK), and class II oncoproteins, chimeric transcription factors derived from chromosomal translocations. The blasts of 80-90% of AML-patients are positive for the RTK c-Kit. In about 50% of the 'core binding factor' (CBF)-AMLs, c-Kit harbors additional gain-of-function mutations, whereas the t(15;17)-positive AML-M3 (100% c-Kit positive) presents virtually no c-Kit mutations. In all c-Kit-positive AMLs, c-Kit signaling is activated. Here, we investigated the role of c-Kit in the determination of the leukemic phenotype in a model of CBF-AML and AML-M3. We studied the role of aberrant c-Kit signaling on normal and leukemic murine stem cells by RNA interference, the c-Kit-inhibitor Imatinib and a constitutively-activated c-Kit mutant in well-established stem cell assays. Effects of the AML-M3-associated PML/RARalpha and the AML-1/ETO as a model for CBF-AML on c-Kit signaling were investigated in trans-activation assays on the Kit promoter. The contribution of activated c-Kit signaling to PML/RARalpha- and AML-1/ETO-induced leukemogenesis was investigated in a murine transduction/transplantation leukemia model. We report that: i) the inhibition of c-Kit impaired the stem cell capacity of PML/RARalpha- and AML-1/ETO-positive HSC; ii) PML/RARalpha was able to activate the c-Kit promoter; iii) constitutively-activated c-Kit increased the stem cell capacity of HSC; and iv) constitutively-activated c-Kit increased the leukemogenic potential of PML/RARalpha- and AML-1/ETO-positive HSC. Our data provide evidence that c-Kit does not have to be mutated to contribute to the determination of the leukemic phenotype in AML.
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PMID:Cooperation between constitutively activated c-Kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells. 1942 69

Isochromosome of the long arm of the derivative chromosome 17, originating from the translocation t(15;17) [ider(17)(q10)t(15;17) or ider(17q)] in acute promyelocytic leukemia (APL), is a rare chromosome aberration which has been associated with a poor prognosis. In the present study, we report on 4 male APL patients with ider(17q) and review the clinical, cytogenetic and molecular characteristics of all previously reported APL patients with ider(17q) in order to clarify the clinical features and outcome of these patients. The data presented in this study demonstrated that ider(17q), which resulted in an extra RARA-PML fusion gene, was more frequent in males than females (male/female ratio of 2.12/1), was associated with a rather low initial white blood cell count and did not confer an adverse prognosis in APL patients treated with all-trans-retinoic acid and chemotherapy. The most frequent additional chromosome change to ider(17q) was trisomy 8. Ider(17q) was observed in all subtypes of the PML-RARA fusion gene, but the frequency of the bcr1 subtype was increased. Cases of overrepresentation of the RARA-PML fusion gene and ider(17q) cases may help in elucidating the role of RARA-PML in leukemogenesis.
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PMID:Isochromosome der(17)(q10)t(15;17) in acute promyelocytic leukemia resulting in an additional copy of the RARA-PML fusion gene: report of 4 cases and review of the literature. 2022 68


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