Alkyl and alk-1-enyl ethers of glycerol in lipids from normal and neoplastic human tissues.
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Adolescent↗
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Alkoxylipids. 3. Naturally occurring D(+)-I-O-cis-alk-I'-enyl-diglycerides.
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Chemical Phenomena↗
Biosynthesis of plasmenylethanolamine (1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine) in the guinea pig heart.
In this study, the isolated guinea pig heart was pulse-labeled with a precursor of ethanolamine glycerophospholipid, and then chased with the non-radioactive compound for 0-8 h. Labeling with hexadecanol revealed that plasmanylethanolamine was the immediate precursor of plasmenylethanolamine, but a substantial portion of the label was also found in phosphatidylethanolamine. When ethanolamine was used as the precursor, the labeling of plasmenylethanolamine was between 50-65% of the labeling of phosphatidylethanolamine, and this ratio was maintained throughout the perfusion. The ratio of labeling is similar to the ratio of pool sizes of these ethanolamine glycerophospholipid in the heart, which implies that the CDP-ethanolamine pathway is also important for plasmenylethanolamine biosynthesis. The role of diradylglycerol in the synthesis of each ethanolamine glycerophospholipid was also investigated. The ratio of 1-alkenyl-2-acyl glycerol to total diradylglycerol content was 7% in the homogenate and 32% in the microsomes. However, ethanolamine phosphotransferase displayed a distinct selectivity towards 1-alkenyl-2-acyl glycerol. Kinetic studies revealed that the synthesis of phosphatidylethanolamine was inhibited by 1-alkenyl-2-acyl glycerol, but the formation of plasmenylethanolamine was not affected by 1,2-diacylglycerol. In addition, the inhibition of ethanolamine phosphotransferase by 1-alkyl-2-acyl glycerol appears to be an important mechanism for the coordination of plasmenylethanolamine biosynthesis via the desaturase reaction and the CDP-ethanolamine pathway.
Animals↗
NPM-ALK gene fusion and Hodgkin's disease.
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Anaplastic Lymphoma Kinase↗
Dephosphorylation and benzoylation reactions occurring in the benzoolysis of diacyl-, alkylacyl-, alk-1-enylacyl-, and acyl-lyso-glycerophosphocholines.
Series of benzoolysis experiments with 1,2-dipalmitoyl glycerophosphocholine (GPC), 1-palmitoyl-2-lyso GPC, and 1-O-hexadecenyl-2-oleoyl GPC, as well as a few experiments with 1-oleoyl-2-acetyl GPC and 1-O-hexadecyl-2-acetyl GPC are reported. The results are used to present a consistent picture of the various dephosphorylation and benzoylation reactions occurring in molten benzoic anhydride.
Acylation↗
Metabolic studies on 1-alkyl- and 1-alk-1'-enyl-glycerophosphatides in the brain.
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Animals↗
The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation.
Anaplastic large cell lymphoma (ALCL) is clinically and pathologically heterogeneous, leading to some difficulty in its diagnosis and acceptance as a specific entity. ALCL can be subdivided into different groups according to histologic features (pleomorphic, monomorphic, small cell predominant, Hodgkin's disease-related, and other less common variants), immunophenotype (T, null, B, and rarely B and T), and clinical features (systemic, primary cutaneous type, ALCL arising in HIV-positive patients, and ALCL occurring after another lymphoproliferative process, such as lymphomatoid papulosis, mycosis fungoides, and Hodgkin's disease. Cytogenetic studies and subsequent cloning of the translocation t(2;5) have shown a high degree of association with Ki-1-positive lymphoma but have revealed that this genetic abnormality is not specific for anaplastic morphologic features, is more common in the monomorphic and small cell variants, and is rare in primary cutaneous ALCL. It is likely that this t(2;5)-positive group is pathogenetically related. The purpose of this article is to review the pathologic and clinical spectrum of ALCL, including the borderline with Hodgkin's disease and lymphomatoid papulosis and to discuss the use of the t(2;5) in better defining a more specific molecular pathologic entity within this group of diseases with CD30 expression.
Anaplastic Lymphoma Kinase↗
Studies on phosphatidylserine by tandem quadrupole and multiple stage quadrupole ion-trap mass spectrometry with electrospray ionization: structural characterization and the fragmentation processes.
Low-energy CAD product-ion spectra of various molecular species of phosphatidylserine (PS) in the forms of [M-H]- and [M-2H+Alk]- in the negative-ion mode, as well as in the forms of [M+H]+, [M+Alk]+, [M-H+2Alk]+, and [M-2H+3Alk]+ (where Alk=Li, Na) in the positive-ion mode contain rich fragment ions that are applicable for structural determination. Following CAD, the [M-H]- ion of PS undergoes dissociation to eliminate the serine moiety (loss of C3H5NO2) to give a [M-H-87]- ion, which equals to the [M-H]- ion of a phoshatidic acid (PA) and give rise to a MS3-spectrum that is identical to the MS2-spectrum of PA. The major fragmentation process for the [M-2H+Alk]- ion of PS arises from primary loss of 87 to give rise to a [M-2H+Alk-87]- ion, followed by loss of fatty acid substituents as acids (RxCO2H, x=1,2) or as alkali salts (e.g., RxCO2Li, x=1,2). These fragmentations result in a greater abundance of [M-2H+Alk-87-R2CO2H]- than [M-2H+Alk-87-R1CO2H]- and a greater abundance of [M-2H+Alk-87-R2CO2Li]- than [M-2H+Alk-87-R1CO2Li]-; while further dissociation of the [M-2H+Alk-87-R2(or 1)CO2Li]- ions gives a preferential formation of the carboxylate anion at sn-1 (R1CO2-) over that at sn-2 (R2CO2-). Other major fragmentation process arises from differential loss of the fatty acid substituents as ketenes (loss of Rx'CH=CO, x=1,2). This results in a more prominent [M-2H+Alk-R2'CH=CO]- ion than [M-2H+Alk-R1'CH=CO]- ion. Ions informative for structural characterization of PS are of low abundance in the MS2-spectra of both the [M+H]+ and the [M+Alk]+ ions, but are abundant in the MS3-spectra. The MS2-spectrum of the [M+Alk]+ ion contains a unique ion corresponding to internal loss of a phosphate group probably via the fragmentation processes involving rearrangement steps. The [M-H+2Alk]+ ion of PS yields a major [M-H+2Alk-87]+ ion, which is equivalent to an alkali adduct ion of a monoalkali salt of PA and gives rise to a greater abundance of [M-H+2Alk-87-R1CO2H]+ than [M-H+2Alk-87-R2CO2H]+. Similarly, the [M-2H+3Alk]+ ion of PS also yields a prominent [M-2H+3Alk-87]+ ion, which undergoes consecutive dissociation processes that involve differential losses of the two fatty acyl substituents. Because all of the above tandem mass spectra contain several sets of ion pairs involving differential losses of the fatty acid substituents as ketenes or as free fatty acids, the identities of the fatty acyl substituents and their positions on the glycerol backbone can be easily assigned by the drastic differences in the abundances of the ions in each pair.
Computer Simulation↗
Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas.
Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
Adolescent↗
Hormonal regulation of expression of growth differentiation factor-9 receptor type I and II genes in the bovine ovarian follicle.
Growth differentiation factor-9 (GDF-9) and bone morphogenetic proteins (BMPs) are crucial factors in follicular growth and development. GDF-9 and BMPs initiate signaling by assembling type I (ALK-3, ALK-5 and ALK-6) and type II (BMPRII) receptors. However, the mechanism regulating the expression of these receptors in the process of bovine follicle development is still unknown. The aim of the present study was to clarify the involvement of receptor systems for GDF-9 and BMPs in follicular selection by examining the effects of FSH and estradiol-17beta (E2) on the regulation of BMPRII, ALK-3, ALK-5 and ALK-6 mRNA expression in bovine granulosa cells (GCs). To observe mRNA expression during follicular development, follicles were obtained from heifers and classified into two groups: pre-selection follicles (PRFs) (an average of 7.7 mm follicles with low E2) and post-selection follicles (POFs) (an average of 15 mm follicles with high E2). Theca layer cells (TCs) and GCs were harvested from aspirated follicles. For in vitro studies, GCs were obtained from bovine follicles of 4-7 mm diameter and cultured in Dulbecco's modified Eagle's/F12 (DMEM/F-12) medium with 10% fetal calf serum for 24 h. The medium was then replaced with serum-free DMEM/F-12 supplemented with different doses of E2 (1, 10, 100 ng/ml) or FSH (1, 5, 10 ng/ml) or combinations of 1 ng/ml of E2 with different FSH doses. Total RNA was extracted and the mRNA expression of BMPRII, ALK-3, ALK-5 and ALK-6 was estimated by the quantitative real-time PCR method using a LightCycler. BMPRII and ALK-5 expression was significantly higher in the GCs of POFs than in those of PRFs, whereas ALK-3 expression was significantly lower in the GCs of POFs than in those of PRFs. There was no difference in ALK-6 expression in GCs between PRFs and POFs. The expression of BMPRII, ALK-5, ALK-3 and ALK-6 genes in the TCs was not significantly different between PRFs and POFs. Treatment of GCs with E2 alone increased BMPRII mRNA expression at a concentration of 100 ng/ml and ALK-5 mRNA expression at 10 ng/ml. BMPRII and ALK-5 mRNA levels were up-regulated by the combination of E2 (1 ng/ml) and FSH (5 ng/ml). On the other hand, FSH alone down-regulated the expression of BMPRII and ALK-5 in GCs. The results of the present study provide the first evidence that FSH and E2 regulate the expression of BMPRII and ALK-5 genes in bovine GCs. Thus, our data suggest that the GDF-9/BMPRII/ALK-5 system may be critically involved in the process of selection of bovine follicles.
Activin Receptors, Type I↗
Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4.
Bone morphogenetic proteins (BMPs) are multifunctional proteins, structurally related to transforming growth factor-beta (TGF-beta) and activin. TGF-beta and activin exert their effects by forming heteromeric complexes of type I and type II serine/threonine kinase receptors. We have previously identified a series of type I serine/threonine kinase receptors, termed activin receptor-like kinase (ALK)-1 to -6. ALK-5 is a TGF-beta type I receptor, whereas ALK-2 and ALK-4 are activin type I receptors. Here we investigated the binding of proteins in the BMP family to ALKs. In transfected COS cells, the binding of osteogenic protein (OP)-1 and BMP-4 to certain ALKs was observed in the absence of type II receptors, and their binding was increased after co-transfection of a BMP type II receptor from Caenorhabditis elegans, DAF-4. OP-1 bound to ALK-2 and ALK-6 efficiently, and to ALK-3 less efficiently, whereas BMP-4 bound to ALK-3 and ALK-6 efficiently. Similarly, OP-1 bound to ALK-2, ALK-3, and/or ALK-6 in various nontransfected cell lines, although the binding profiles were different between different cell types. BMP-4 bound to ALK-3 in MC3T3-E1 osteoblasts and human foreskin fibroblasts. These results suggest that ALK-3 and ALK-6 are type I receptors for OP-1 and BMP-4; in addition, ALK-2 is a type I receptor shared by activin and OP-1, but not by BMP-4.
Activin Receptors↗
TIMP-1 expression in anaplastic large cell lymphoma is usually restricted to macrophages and only seldom observed in tumour cells.
Anaplastic large cell lymphomas (ALCLs) can be subdivided into two subgroups on the basis of their expression of the ALK protein. ALK protein expression leads to activation of signal transducer and activator of transcription (STAT) 3, which is more commonly expressed in ALK-positive than in ALK-negative tumours. Activated STAT3 leads to the induction of several genes such as Mcl-1, Bcl-2 and Bcl-X(L), and tissue inhibitor of metalloproteinase (TIMP)-1. In this study, we analysed TIMP-1 expression in five ALCL cell lines and 11 tumours by quantitative RT-PCR and immunohistochemistry. We identified high-level TIMP-1 expression by RT-PCR in three ALK-positive ALCL-derived cell lines and in all ALK-positive ALCLs, whereas ALK-negative ALCLs generally demonstrated a lower level of TIMP-1 expression. Concordant with these results, we observed TIMP-1 immunostaining in all ALK-positive ALCLs and in only two of six ALK-negative ALCLs. No relationship was observed between the levels of ALK and TIMP-1 expression in the ALK-positive tumours. STAT3 expression levels were similar in all ALCL samples. Double staining with either CD30 or CD68 demonstrated that TIMP-1 expression was restricted to macrophages in the majority of TIMP-1-positive tumours. Expression of the TIMP-1 substrate MMP-2 was more prominent in ALK-negative tumours, while MMP-9 levels were low in all cases. Expression levels of IL-6 and TGF-beta1, which are cytokines known to induce TIMP-1, were higher in ALK-negative ALCLs and moderate in ALK-positive tumours. No clear relationship was observed between IL-10 expression and ALK positivity. Overall, no correlation was seen in ALCLs between the expression of TIMP-1 and that of cytokines that induce TIMP-1. Lack of TIMP-1 expression in the tumour cells of ALK-positive ALCLs argues against a direct role for ALK-induced activation of STAT3 in the regulation of TIMP-1 expression in ALCL.
Anaplastic Lymphoma Kinase↗
Intrinsic apoptotic pathway in anaplastic large cell lymphoma.
Anaplastic large cell lymphoma (ALCL) includes a subset of tumors that has abnormalities of chromosome 2p23, resulting in overexpression of anaplastic lymphoma kinase (ALK). Previous studies have reported differences in apoptotic rate and expression levels of apoptosis regulatory proteins between ALK+ and ALK- ALCL. In this study, we assessed for expression of the intrinsic apoptotic pathway proteins cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 in 2 ALK+ ALCL cell lines and 42 ALCL tumors (17 ALK+, 25 ALK-). We used the Karpas 299 and SU-DHL-1 cell lines, and the inhibitors Z-LEHD-FMK (specific for caspase 9) and Boc-D-FMK (general caspase inhibitor) to investigate the role of caspase 9 activation in chemotherapy-induced apoptotic cell death. Caspase 9 activity was significantly increased in Karpas-299 and SU-DHL-1 cells after chemotherapy treatment, but remained as low as control levels with addition of either caspase inhibitor. Both caspase inhibitors rescued a substantial fraction of Karpas 299 and SU-DHL-1 cells from drug-induced cell death. In ALCL tumors, expression of cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 was also assessed and correlated with apoptotic rate and activated caspase 3 levels. Cytochrome c was expressed in all 13 (100%) ALK+ and 18 (95%) of 19 ALK- ALCL tumors. Apoptosis protease-activating factor 1 was detected in 14 (88%) of 16 ALK+ and 19 (79%) of 24 ALK- ALCL tumors. Procaspase 9 was expressed in 5 (30%) of 17 ALK+ and 2 (8%) of 25 ALK- ALCL tumors (P = .09). In the entire study group (ALK+ and ALK- ALCL), procaspase 9 expression levels significantly correlated with apoptotic rate (P = .02) and activated caspase 3 levels (P = .05). This correlation could not be shown in the ALK+ or ALK- ALCL subgroups, presumably because of the small sample size. In conclusion, chemotherapy-induced cell death in ALK+ ALCL cells involves the intrinsic apoptotic pathway, and apoptosome function may be an important determinant of apoptosis in ALCL tumors.
Anaplastic Lymphoma Kinase↗
Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells.
Transforming growth factor-beta (TGF-beta) plays a crucial role in vascular development and homeostasis by regulating many transcriptional targets. Activin receptor-like kinase 5 (ALK-5) is a TGF-beta type I receptor expressed in various TGF-beta-responsive cells. In contrast, ALK-1 functions as a TGF-beta type I receptor in endothelial cells, and is responsible for human hereditary hemorrhagic telangiectasia (HHT) type II. ALK-5 and ALK-1 mediate TGF-beta signals through distinct Smad proteins, i.e., Smad2/Smad3 and Smad1/Smad5, respectively. To identify target genes of ALK-1 and ALK-5 in endothelial cells, we conducted oligonucleotide microarray analysis. Human umbilical vein endothelial cells (HUVEC) were infected with recombinant adenoviruses carrying a constitutively active form of ALK-1 or ALK-5. ALK-5 inhibited the proliferation, network formation, and tube formation of HUVEC and induced their apoptosis, whereas ALK-1 did not exhibit significant effects on HUVEC in vitro. mRNAs were extracted from HUVEC and used for hybridization of oligonucleotide arrays representing approximately 7,000 human genes. Northern blot and quantitative real-time polymerase chain reaction (PCR) analyses were also performed for some of these genes, confirming the validity of this microarray analysis. We found that ALK-1 specifically upregulated Smad6, Smad7, Id1, Id2, endoglin, STAT1, and interleukin 1 receptor-like 1. ALK-5, in contrast, upregulated PlGF, SM22alpha, connexin 37, betaIG-H3, and LTBP1. ALK-1 downregulated Smad1, CXCR4, Ephrin-A1, and plakoglobin, whereas ALK-5 downregulated claudin 5 and integrin beta(5). These results revealed some new targets of TGF-beta in endothelial cells, and differences in transcriptional regulation patterns between ALK-1 and ALK-5.
Activin Receptors, Type I↗
Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis.
Bone morphogenetic proteins (BMPs) are multifunctional proteins structurally related to transforming growth factor-beta (TGF beta) and activin that can induce cartilage and bone growth in vivo. Members of the TGF beta superfamily exert their biological effects via heteromeric serine/threonine kinase complexes of type I and type II receptors. We previously obtained six different type I receptors, termed activin receptor-like kinase-1 (ALK-1) to -6. ALK-5 is a TGF beta type I receptor, ALK-2 and ALK-4 are activin type I receptors, and ALK-3 and ALK-6 are type I receptors for osteogenic protein-1 (OP-1)/bone morphogenetic protein-7 (BMP-7) and BMP-4. Here we report the complementary DNA cloning of the mouse homolog of ALK-3, which is highly conserved between mouse and man. ALK-3 messenger RNA (mRNA) is ubiquitously expressed in various adult mouse tissues, whereas ALK-6 mRNA is only found in brain and lung. The distribution of ALK-3 and ALK-6 mRNA in the postimplantation mouse embryo [6.5-15.5 days postcoitum (pc)] was studied by in situ hybridization. ALK-3 was nearly ubiquitously expressed throughout these stages of development, but was notably absent in the liver. In contrast, ALK-6 showed a more restricted expression pattern. ALK-6 mRNA was absent in early postimplantation embryos, was detected first in 9.5 days pc embryos, and persisted until 15.5 days pc. In midgestation embryos, ALK-6 transcripts were detected in mesenchymal precartilage condensations, premuscle masses, blood vessels, central nervous system, parts of the developing ear and eye, and epithelium. The expression in sites of developing cartilage and bone supports the idea that ALK-3 and -6 are receptors for BMPs in vivo. In addition, the expression of these genes in many soft tissues suggests broader functions for BMPs in embryogenesis.
Activin Receptors↗
Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells.
Sphingomyelin (SM) metabolism in the gut has been implicated in colonic tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in the intestinal content and at the brush border. The enzyme activity is decreased in the tissues of human colorectal tumours. This study examines whether site or chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells. Total RNA was isolated and the cDNA of alk-SMase was amplified by RT-PCR. The size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA. DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells. No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4 deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2 cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS-7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase. The deleted region included residue His353, which is predicted to form a substrate-binding site of alk-SMase. H353A substitution resulted in a protein with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells the alk-SMase activities were low. However, to culture the cells under polarizing conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The alk-SMase activity varied in parallel with alkaline phosphatase activity. In conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a differentiation-related expression of the enzyme in Caco-2 cells. The results provide a molecular mechanism related to previous findings of reduced alk-SMase activity in human colon cancers.
Alkaline Phosphatase↗
Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, initially discovered as part of the NPM-ALK fusion protein, resulting from the t(2;5) translocation that is frequently associated with anaplastic large-cell lymphomas. The native ALK protein is normally expressed in the developing and, at a weaker level, adult nervous system. We recently demonstrated that the oncogenic, constitutively kinase-activated NPM-ALK protein was antiapoptotic when expressed in Jurkat lymphoblastic cells treated with cytotoxic drugs. In contrast, we now show that Jurkat cells overexpressing the wild-type ALK receptor are more sensitive to doxorubicin-induced apoptosis than parental cells. Moreover, the ALK protein is cleaved during apoptosis in a caspase-dependent manner. Mutation of aspartic residues to asparagine allowed us to map the caspase cleavage site in the juxtamembrane region of ALK. In order to assess the role of ALK in neural cell-derived tissue, we transiently expressed ALK in the 13.S.1.24 rat neuroblast immortalized cell line. ALK expression led to apoptotic cell death of the neuroblasts. ALK ligation by specific activating antibodies decreased ALK-facilitated apoptosis in both lymphoid and neuronal cell lines. Moreover, ALK transfection reduced the survival of primary cultures of cortical neurons. Thus, ALK has a proapoptotic activity in the absence of ligand, whereas it is antiapoptotic in the presence of its ligand and when the kinase is intrinsically activated. These properties place ALK in the growing family of dependence receptors.
Anaplastic Lymphoma Kinase↗
Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells.
The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)-derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)-independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.
Anaplastic Lymphoma Kinase↗