scholarly journals Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs

2021 ◽  
Vol 12 ◽  
Author(s):  
Salman M. Toor ◽  
Sachin Wani ◽  
Omar M. E. Albagha
Keyword(s):  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Differentially Expressed ◽  
Mineral Density ◽  
Murine Bone Marrow ◽  
Skeletal Mass ◽  
International Mouse Phenotyping Consortium ◽  
Non Coding Rnas ◽  
Immune Related Genes

Osteoclasts are the sole bone resorbing cells, which undertake opposing roles to osteoblasts to affect skeletal mass and structure. However, unraveling the comprehensive molecular mechanisms behind osteoclast differentiation is necessitated to overcome limitations and scarcity of available data, particularly in relation with the emerging roles of long non-coding RNAs (LncRNAs) in gene expression. In this study, we performed comprehensive and progressive analyses of the dynamic transcriptomes of murine osteoclasts, generated in vitro. We compared the total RNA-based transcriptomes of murine bone marrow derived cells with differentiated osteoclasts, while focusing on potentially novel genes and LncRNAs, to uncover critical genes and their associated pathways, which are differentially regulated during osteoclast differentiation. We found 4,214 differentially regulated genes during osteoclast differentiation, which included various types of LncRNAs. Among the upregulated protein coding genes not previously associated with osteoclast are Pheta1, Hagh, Gfpt1 and Nol4, while downregulated genes included Plau, Ltf, Sell and Zfp831. Notably, we report Nol4 as a novel gene related to osteoclast activity since Nol4 knockout mice Nol4em1(International Mouse Phenotyping Consortium)J exhibit increased bone mineral density. Moreover, the differentially expressed LncRNAs included antisense and long intergenic non-coding RNAs, among others. Overall, immune-related and metabolism-related genes were downregulated, while anatomical morphogenesis and remodeling-related genes were upregulated in early-differentiated osteoclasts with sustained downregulation of immune-related genes in mature osteoclasts. The gene signatures and the comprehensive transcriptome of osteoclast differentiation provided herein can serve as an invaluable resource for deciphering gene dysregulation in osteoclast-related pathologic conditions.

scholarly journals Overexpression of PIK3R1 Promotes Bone Formation by Regulating Osteoblast Differentiation and Osteoclast Formation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Haitao Zhu ◽  
Hua Chen ◽  
Degang Ding ◽  
Shui Wang ◽  
Xiaofeng Dai ◽  
...  
Keyword(s):  
Bone Formation ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Differentially Expressed ◽  
Estrogen Signaling ◽  
Mineral Density

In an effort to bolster our understanding of regulation of bone formation in the context of osteoporosis, we screened out differentially expressed genes in osteoporosis patients with high and low bone mineral density by bioinformatics analysis. PIK3R1 is increasingly being nominated as a pivotal mediator in the differentiation of osteoblasts and osteoclasts that is closely related to bone formation. However, the specific mechanisms underlying the way that PIK3R1 affects bone metabolism are not fully elucidated. We intended to examine the potential mechanism by which PIK3R1 regulates osteoblast differentiation. Enrichment analysis was therefore carried out for differentially expressed genes. We noted that the estrogen signaling pathway, TNF signaling pathway, and osteoclast differentiation were markedly associated with ossification, and they displayed enrichment in PIK3R1. Based on western blot, qRT-PCR, and differentiation analysis in vitro, we found that upregulation of PIK3R1 enhanced osteoblastic differentiation, as evidenced by increased levels of investigated osteoblast-related genes as well as activities of ALP and ARS, while it notably decreased levels of investigated osteoclast-related genes. On the contrary, downregulation of PIK3R1 decreased levels of osteoblast-related genes and increased levels of osteoclast-related genes. Besides, in vitro experiments revealed that PIK3R1 facilitated proliferation and repressed apoptosis of osteoblasts but had an opposite impact on osteoclasts. In summary, PIK3R1 exhibits an osteoprotective effect via regulating osteoblast differentiation, which can be represented as a promising therapeutic target for osteoporosis.

scholarly journals Osteoprotective Effects of Loganic Acid on Osteoblastic and Osteoclastic Cells and Osteoporosis-Induced Mice

2020 ◽  
Vol 22 (1) ◽  
pp. 233
Author(s):  
Eunkuk Park ◽  
Chang Gun Lee ◽  
Eunguk Lim ◽  
Seokjin Hwang ◽  
Seung Hee Yun ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Osteoblastic Differentiation ◽  
Common Disease ◽  
Root Extract ◽  
Mouse Bone Marrow ◽  
Mineral Density ◽  
Bone Mineral Density Loss ◽  
In Vivo Experiments

Osteoporosis is a common disease caused by an imbalance of processes between bone resorption by osteoclasts and bone formation by osteoblasts in postmenopausal women. The roots of Gentiana lutea L. (GL) are reported to have beneficial effects on various human diseases related to liver functions and gastrointestinal motility, as well as on arthritis. Here, we fractionated and isolated bioactive constituent(s) responsible for anti-osteoporotic effects of GL root extract. A single phytochemical compound, loganic acid, was identified as a candidate osteoprotective agent. Its anti-osteoporotic effects were examined in vitro and in vivo. Treatment with loganic acid significantly increased osteoblastic differentiation in preosteoblast MC3T3-E1 cells by promoting alkaline phosphatase activity and increasing mRNA expression levels of bone metabolic markers such as Alpl, Bglap, and Sp7. However, loganic acid inhibited osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. For in vivo experiments, the effect of loganic acid on ovariectomized (OVX) mice was examined for 12 weeks. Loganic acid prevented OVX-induced bone mineral density loss and improved bone structural properties in osteoporotic model mice. These results suggest that loganic acid may be a potential therapeutic candidate for treatment of osteoporosis.

scholarly journals Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Minsun Kim ◽  
MinBeom Kim ◽  
Jae-Hyun Kim ◽  
SooYeon Hong ◽  
Dong Hee Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Rat Model ◽  
Osteoclast Differentiation ◽  
Ovariectomized Rat ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mineral Density ◽  
Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

scholarly journals Prognostic Value and Regulatory Network of Immune-Related Genes in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Xiang Zhou ◽  
Keying Zhang ◽  
Fa Yang ◽  
Chao Xu ◽  
Jianhua Jiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regression Analysis ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Risk Model ◽  
Cox Regression ◽  
Wilcoxon Test ◽  
Differentially Expressed ◽  
Cox Regression Analysis ◽  
Immune Related Genes

Abstract Background: Hepatocellular carcinoma (HCC) is a disease with higher morbidity, mortality, and poor prognosis in the whole world. Understanding the crosslink between HCC and the immune system is essential for people to uncover a few potential and valuable therapeutic strategies. This study aimed to reveal the correlation between HCC and immune-related genes and establish a clinical evaluation model. Methods: We had analyzed the clinical information consisted of 373 HCC and 49 normal samples from the cancer genome atlas (TCGA). The differentially expressed genes (DEGs) were selected by the Wilcoxon test and the immune-related differentially expressed genes (IRDEGs) in DEGs were identified by matching DEGs with immune-related genes downloaded from the ImmPort database. Furthermore, the univariate Cox regression analysis and multivariate Cox regression analysis were performed to construct a prognostic risk model. Then, twenty-two types of tumor immune-infiltrating cells (TIICs) were downloaded from Tumor Immune Estimation Resource (TIMER) and were used to construct the correlational graphs between the TIICs and risk score by the CIBERSORT. Subsequently, the transcription factors (TFs) were gained in the Cistrome website and the differentially expressed TFs (DETFs) were achieved. Finally, the KEGG pathway analysis and GO analysis were performed to further understand the molecular mechanisms between DETFs and PDIRGs.Results: In our study, 5839 DEGs, 326 IRDEGs, and 31 prognosis-related IRDEGs (PIRDEGs) were identified. And 8 optimal PIRDEGs were employed to construct a prognostic risk model by multivariate Cox regression analysis. The correlation between risk genes and clinical characterizations and TIICs has verified that the prognostic model was effective in predicting the prognosis of HCC patients. Finally, several important immune-related pathways and molecular functions of the eight PIRDEGs were significantly enriched and there was a distinct association between the risk IRDEGs and TFs. Conclusion: The prognostic risk model showed a more valuable predicting role for HCC patients, and produced many novel therapeutic targets and strategies for HCC.

scholarly journals Long Non-coding RNAs RN7SK and GAS5 Regulate Macrophage Polarization and Innate Immune Responses

2020 ◽  
Vol 11 ◽  
Author(s):  
Imran Ahmad ◽  
Araceli Valverde ◽  
Raza Ali Naqvi ◽  
Afsar R. Naqvi
Keyword(s):  
Immune Responses ◽  
Epigenetic Regulation ◽  
Innate Immune ◽  
Differentially Expressed ◽  
Immune Functions ◽  
Innate Immune Responses ◽  
Antigen Uptake ◽  
Non Coding Rnas

Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

scholarly journals Tetracycline Analogs Inhibit Osteoclast Differentiation by Suppressing MMP-9-Mediated Histone H3 Cleavage

2019 ◽  
Vol 20 (16) ◽  
pp. 4038 ◽  
Author(s):  
Yeojin Kim ◽  
Jinman Kim ◽  
Hyerim Lee ◽  
Woo-Ri Shin ◽  
Sheunghun Lee ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Histone H3 ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Receptor Activator ◽  
New Strategy ◽  
Docking Approach ◽  
Metalloproteinase 9

Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.

scholarly journals Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Loss via Regulation of Akt/GSK3β/PTEN/NFATc1 Signaling Pathway and Calcineurin Activity

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 345 ◽  
Author(s):  
Sheng-Hua Lu ◽  
Yi-Jan Hsia ◽  
Kuang-Chung Shih ◽  
Tz-Chong Chou
Keyword(s):  
Bone Loss ◽  
Molecular Mechanisms ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Calcineurin Activity

Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.

scholarly journals Transcriptomic Analysis of mRNA-lncRNA-miRNA Interactions in Hepatocellular Carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xia Tang ◽  
Delong Feng ◽  
Min Li ◽  
Jinxue Zhou ◽  
Xiaoyuan Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Rna Seq ◽  
Pairwise Interactions ◽  
Micro Rnas ◽  
Non Coding Rnas ◽  
First Time

Abstract Fully elucidating the molecular mechanisms of non-coding RNAs (ncRNAs), including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), underlying hepatocarcinogenesis is challenging. We characterized the expression profiles of ncRNAs and constructed a regulatory mRNA-lncRNA-miRNA (MLMI) network based on transcriptome sequencing (RNA-seq) of hepatocellular carcinoma (HCC, n = 9) patients. Of the identified miRNAs (n = 203) and lncRNAs (n = 1,090), we found 16 significantly differentially expressed (DE) miRNAs and three DE lncRNAs. The DE RNAs were highly enriched in 21 functional pathways implicated in HCC (p < 0.05), including p53, MAPK, and NAFLD signaling. Potential pairwise interactions between DE ncRNAs and mRNAs were fully characterized using in silico prediction and experimentally-validated evidence. We for the first time constructed a MLMI network of reciprocal interactions for 16 miRNAs, three lncRNAs, and 253 mRNAs in HCC. The predominant role of MEG3 in the MLMI network was validated by its overexpression in vitro that the expression levels of a proportion of MEG3-targeted miRNAs and mRNAs was changed significantly. Our results suggested that the comprehensive MLMI network synergistically modulated carcinogenesis, and the crosstalk of the network provides a new avenue to accurately describe the molecular mechanisms of hepatocarcinogenesis.

scholarly journals Transcriptome profiling of peanut (Arachis hypogaea) gynophores in gravitropic response

2013 ◽  
Vol 40 (12) ◽  
pp. 1249 ◽  
Author(s):  
Hai-fen Li ◽  
Xiao-Ping Chen ◽  
Fang-he Zhu ◽  
Hai-Yan Liu ◽  
Yan-Bin Hong ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Arachis Hypogaea ◽  
Molecular Mechanisms ◽  
Carbon Fixation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pentose Phosphate ◽  
Differentially Expressed ◽  
Pcr Analysis

Peanut (Arachis hypogaea L.) produces flowers aerially, but the fruit develops underground. This process is mediated by the gynophore, which always grows vertically downwards. The genetic basis underlying gravitropic bending of gynophores is not well understood. To identify genes related to gynophore gravitropism, gene expression profiles of gynophores cultured in vitro with tip pointing upward (gravitropic stimulation sample) and downward (control) at both 6 and 12 h were compared through a high-density peanut microarray. After gravitropic stimulation, there were 174 differentially expressed genes, including 91 upregulated and 83 downregulated genes at 6 h, and 491 differentially expressed genes including 129 upregulated and 362 downregulated genes at 12 h. The differentially expressed genes identified were assigned to 24 functional categories. Twenty pathways including carbon fixation, aminoacyl-tRNA biosynthesis, pentose phosphate pathway, starch and sucrose metabolism were identified. The quantitative real-time PCR analysis was performed for validation of microarray results. Our study paves the way to better understand the molecular mechanisms underlying the peanut gynophore gravitropism.

Differentially Expressed and Novel Transcripts in Highly Purified Chronic Phase CML Stem Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 193-193
Author(s):  
Yun Zhao ◽  
Allen Delaney ◽  
Afshin Raouf ◽  
Kamini Raghuram ◽  
Haiyan I Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Chronic Phase ◽  
Differentially Expressed ◽  
Pcr Analysis ◽  
Direct Role ◽  
Hematopoietic Stem ◽  
Transcript Levels

Abstract The chronic phase of CML is sustained by rare BCR-ABL+ stem cells. These cells share many properties with normal pluripotent hematopoietic stem cells, but also differ in critical ways that alter their growth, drug responsiveness and genome stability. Understanding the molecular mechanisms underlying the biological differences between normal and CML stem cells is key to the development of more effective CML therapies. To obtain new insights into these mechanisms, we generated Long Serial Analysis of Gene Expression (SAGE) libraries from paired isolates of highly purified lin-CD34+CD45RA-CD36- CD71-CD7-CD38+ and lin-CD34+CD45RA-CD36-CD71-CD7-CD38- cells from 3 chronic phase CML patients (all with predominantly Ph+/BCR-ABL+ cells in both subsets) and from 3 control samples: a pool of 10 normal bone marrows (BMs), a single normal BM and a pool of G-CSF-mobilized blood cells from 9 donors. In vitro bioassays showed the CD34+CD38+ cells were enriched in CFCs (CML: 3–20% pure; normal: 4–19% pure) and the CD34+CD38- cells were enriched in LTC-ICs (CML: 0.2–26% pure; normal: 12–52% pure). Each of the 12 libraries was then sequenced to a depth of ~200,000 tags and tags from libraries prepared from like phenotypes were compared between genotypes using DiscoverySpace software and hierarchical clustering. 1687 (355 with clustering) and 1258 (316 with clustering) transcripts were thus identified as differentially expressed in the CML vs control CD34+CD38− and CD34+CD38+ subsets, respectively. 266 of these transcripts (11 with clustering) were differentially expressed in both subsets. The differential expression of 5 genes (GAS2, IGF2BP2, IL1R1, DUSP1 & SELL) was confirmed by real-time PCR analysis of lin-CD34+ cells isolated from an additional 5 normal BMs and 11 CMLs, and lin-CD34+CD38− cells from an additional 2 normal BMs and 2 CMLs (with dominant Ph+ cells). GAS2 and IL1R1 transcript levels were correlated with BCR-ABL transcript levels in both primitive subsets, and predicted differences in expression of IL1R1 and SELL were apparent within 3 days in CD34+ cord blood cells transduced with a lenti-BCR-ABL-IRES-GFP vs a control lenti-GFP vector (n=3). These findings support a direct role of BCR-ABL in perturbing the expression of these 3 genes. Further comparison of the meta CD34+CD38− and CD34+CD38+ CML cell libraries with most publicly accessible SAGE data revealed 69 novel tags in the CD34+ CML cells that correspond to unique but conserved genomic sequences. Nine of these were recovered by 5′- and 3′- RACE applied to cDNAs pooled from several human leukemic cell lines. These results illustrate the power of SAGE to reveal key components of the transcriptomes of rare human CML stem cell populations including transcripts of genes not previously known to exist. Continuing investigation of their biological roles in primary CML cells and primitive BCR-ABL-transduced human cells offer important strategies for delineating their potential as therapeutic targets.

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