Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inv(16)(p13q22) is associated with acute myeloid leukemia subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This chromosomal rearrangement results in the fusion of CBFB and MYH11 genes. CBF beta normally interacts with RUNX1 to form a transcriptionally active nuclear complex. The MYH11 gene encodes the smooth muscle myosin heavy chain. The CBF beta-SMMHC fusion protein is capable of binding to RUNX1 and form dimers and multimers through its myosin tail. Previous results from transgenic mouse models show that Cbfb-MYH11 is able to inhibit dominantly Runx1 function in hematopoiesis, and is a key player in the pathogenesis of leukemia. In recent years, molecular and cellular biological studies have led to the proposal of several models to explain the function of CBF beta-SMMHC. In this review, we will first focus our attention on the molecular mechanisms proposed in the recent publications. We will next examine recent gene expression profiling studies on inv(16) leukemia cells. Finally, we will describe a recent study from one of our labs on the identification of cooperating genes for leukemogenesis with CBFB-MYH11.
 ...
PMID:Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. 1515 86

Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia. Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers. Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD. Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002. After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8, PML/RAR alpha, and MYH11/CBF beta were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 10(3) copies/microgram RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients, PML/RAR alpha was expressed in 3 patients, and MYH11/CBF beta was expressed in 1 patient. Four of the 8 patients with AML1/MTG8 expression and all 3 with PML/RAR alpha expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed pesistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR alpha and MYH11/CBF beta fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% +/- 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes. Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.
 ...
PMID:Clinical significance of minimal residual disease in childhood acute myeloid leukemia. 1516 92

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

Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new oncogenic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias. Thyroid carcinomas and myeloid leukemias both possess transcription factor gene rearrangements-PPARgamma-related translocations in thyroid carcinoma and RARalpha-related and CBF-related translocations (amongst others) in myeloid leukemia. PPARgamma and RARalpha are closely related members ofthe same nuclear receptor subfamily, and the PML-RARalpha and PAX8-PPARgamma fusion proteins both function as dominant negative inhibitors of their wild-type parent proteins. Thyroid carcinomas and myeloid leukemias also both harbor NRAS mutations (15-25% of both cancers) and receptor tyrosine kinase mutations--RET mutations in thyroid carcinomas and FLT3 mutations in myeloid leukemias. The NRAS and tyrosine receptor kinase mutations are not observed in the same thyroid carcinoma or leukemia patients, suggesting that multiple initiating pathways exist in both. Lastly, thyroid carcinomas and myeloid leukemias possess p53 mutations at relatively low frequency (10-15%) in patients who tend to be older and have more aggressive, therapy resistant disease. Such parallels are unlikely to occur by chance alone and argue that common mechanisms underlie these diverse epithelial and hematologic cancers. The comparison of thyroid carcinomas and myeloid leukemias may highlight areas of thyroid cancer investigation worthy of further focus. For example, few collaborating mutations have been defined in thyroid carcinomas even though they play a clear role in myeloid leukemias, as exemplified by RARalpha rearrangements and FLT3 mutations that together dictate the promyleocytic leukemia phenotype. Functional interactions between collaborating mutations are possible at multiple levels, and it is tempting to speculate that some thyroid carcinomas might develop through an unique combination or co-activation of RET and RAS and/or RET and PPARgamma (and/or other) signaling systems. In fact, the ELE1-RET (PTC3) fusion protein contains the ELE1 nuclear receptor co-activator domain and it appears to physically associate with and inhibit wild-type PPARgamma in some papillary carcinomas. The similarities of the fusion proteins in thyroid carcinoma and myeloid leukemia suggest that a more directed search for fusion genes in non-thyroid carcinomas is warranted. In fact, novel fusion genes have been identified recently in aggressive midline, secretory breast, and renal cell carcinomas, although the epithelial nature of the latter is not well-documented. Interestingly, these cancers all tend to present more frequently in adolescence and young adulthood in a manner similar to thyroid and myeloid malignancies that have fusion genes. The analyses of cancers that present earlier in life may enhance fusion gene recognition in other carcinoma types. Definition and biologic characterization of the precursor cells that give rise to thyroid carcinoma will also be important. Myeloid leukemias are thought to arise from stem/progenitor cells that acquire disturbed self-renewal and differentiation capacities but retain characteristics of the myeloid lineages. Although the presence of comparable stem/progenitor cells in the thyroid are not defined, distinct thyroid cancer lineages and patterns of differentiation exist and candidate stem/progenitor cells such as the p63-immunoreactive solid cell nests are apparent. A last important area is development of molecular-based therapies for thyroid carcinoma patients resistant to standard radio-iodine treatment. Treatments for such cancers are limited and pathways defined by thyroid cancer mutations are prime targets for pharmacologic interventions with molecular inhibitors. Tyrosine kinase inhibitors and nuclear receptor ligands have proven dramatically effective in some myeloid leukemia patients. Various molecular inhibitors are being investigated now in thyroid cancer models. Such developments predict that the thyroid cancer model will continue to provide biologic insights into human carcinoma biology and that improved pathologic diagnosis and treatment for thyroid cancer patients sit on the not too distant horizon.
 ...
PMID:Molecular events in follicular thyroid tumors. 1620 39

Multiple mechanisms regulate dynamic cytoplasmic-to-nuclear transport of transcription factors. However, little is known about the involvement of cytoskeletal proteins in this process. The heterodimeric transcription factor PEBP2/CBF is composed of a DNA-binding subunit, Runx1, and a non-DNA-binding subunit, PEBP2beta/CBFbeta. The Runx1 protein possesses nuclear localization signals and is found exclusively in the nucleus, whereas PEBP2beta is located in the cytoplasm in most cells and tissues examined thus far. We investigated the mechanism by which PEBP2beta localizes to the cytoplasm and found that it associates with filamin A, an actin-binding cytoskeletal protein. Filamin A retains PEBP2beta in the cytoplasm, thereby hindering its engagement as a Runx1 partner. When filamin A is absent, PEBP2beta moves into the nucleus and enhances Runx1-dependent transcription. These observations highlight the significance of the subcellular localization of PEBP2beta in regulating its activity as a component of the PEBP2/CBF transcription factor. In humans, PEBP2beta is frequently targeted in the leukemia-associated chromosomal abnormality, inversion 16 (inv 16). Thus, identifying the factors that mediate the subcellular localization of the PEBP2beta-derived chimeric transcription factor produced by inv 16 is an important issue that will need to be resolved in order to understand the mechanism(s) involved in inv 16-induced leukemogenesis.
 ...
PMID:Biological implications of filamin A-bound PEBP2beta/CBFbeta retention in the cytoplasm. 1639 Mar 16

RUNX1/AML1, located on chromosome 21, is a key factor in the generation and maintenance of hematopoietic stem cells and the gene most frequently implicated in human leukemias. Chromosome translocations and point mutations are well-documented genetic alterations in RUNX leukemia (also known as CBF leukemia). In addition, overdosage or overexpression of RUNX1 is suspected to be a third mode of RUNX1 involvement in leukemogenesis. The possibility that this mode might underlie Down syndrome-related leukemias caused by trisomy of chromosome 21 is discussed.
 ...
PMID:Increased dosage of the RUNX1/AML1 gene: a third mode of RUNX leukemia? 1639 Mar 18

The acute myeloid leukemia (AML)-associated CBF beta-SMMHC fusion protein impairs hematopoietic differentiation and predisposes to leukemic transformation. The mechanism of leukemia progression, however, is poorly understood. In this study, we report a conditional Cbfb-MYH11 knockin mouse model that develops AML with a median latency of 5 months. Cbf beta-SMMHC expression reduced the multilineage repopulation capacity of hematopoietic stem cells (HSCs) while maintaining their numbers under competitive conditions. The fusion protein induced abnormal myeloid progenitors (AMPs) with limited proliferative potential but leukemic predisposition similar to that of HSCs in transplanted mice. In addition, Cbf beta-SMMHC blocked megakaryocytic maturation at the CFU-Meg to megakaryocyte transition. These data show that a leukemia oncoprotein can inhibit differentiation and proliferation while not affecting the maintenance of long-term HSCs.
 ...
PMID:Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. 1641 72

The gene encoding for core-binding factor beta (CBFbeta) is altered in acute myeloid leukemia samples with an inversion in chromosome 16, expressing the fusion protein CBFbeta-SMMHC. Previous studies have shown that this oncoprotein interferes with hematopoietic differentiation and proliferation and participates in leukemia development. In this study, we provide evidence that Cbfbeta modulates the oncogenic function of this fusion protein. We show that Cbfbeta plays an important role in proliferation of hematopoietic progenitors expressing Cbfbeta-SMMHC in vitro. In addition, Cbfbeta-SMMHC-mediated leukemia development is accelerated in the absence of Cbfbeta. These results indicate that the balance between Cbfbeta and Cbfbeta-SMMHC directly affects leukemia development, and suggest that CBF-specific therapeutic molecules should target CBFbeta-SMMHC function while maintaining CBFbeta activity.
 ...
PMID:Cbfbeta reduces Cbfbeta-SMMHC-associated acute myeloid leukemia in mice. 1714 66

The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myelogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor beta-smooth muscle myosin heavy chain (CBFbeta-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3-treated U937 cells expressing CBFbeta-SMMHC. CBFbeta-SMMHC was shown to displace RUNX1 from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15(INK4b) is a target of CBFbeta-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs.
 ...
PMID:Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBFbeta-SMMHC in acute myelogenous leukemia with inv(16). 1728 31

Both PU.1 (also called SFPI1), an Ets-family transcription factor, and AML1 (also called RUNX1), a DNA-binding subunit of the CBF transcription factor family, are crucial for the generation of all hematopoietic lineages, and both act as tumor suppressors in leukemia. An upstream regulatory element (URE) of PU.1 has both enhancer and repressor activity and tightly regulates PU.1 expression. Here we show that AML1 binds to functionally important sites within the PU.1 upstream regulatory element and regulates PU.1 expression at both embryonic and adult stages of development. Analysis of mice carrying conditional AML1 knockout alleles and knock-in mice carrying mutations in all three AML1 sites of the URE proximal region demonstrated that AML1 regulates PU.1 both positively and negatively in a lineage dependent manner. Dysregulation of PU.1 expression contributed to each of the phenotypes observed in these mice, and restoration of proper PU.1 expression rescued or partially rescued each phenotype. Thus, our data demonstrate that PU.1 is a major downstream target gene of AML1.
 ...
PMID:PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. 1799 17


<< Previous 1 2 3 4 5 6 Next >>