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Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1.

Teo AE, Chen Z, Miranda RN, McDonnell T, Medeiros LJ, McCarty N - Leukemia (2015)

Bottom Line: On PAX5 silencing, the MCL cells displayed upregulated interleukin (IL)-6 expression and increased responses to paracrine IL-6.Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5(-) MCL cells are highly drug-resistant compared with PAX5 wild-type MCL cells.Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B-cell cancer and encourage future efforts to design effective therapies against MCL.

View Article: PubMed Central - PubMed

Affiliation: Center for Stem Cell and Regenerative Medicine, Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, TX, USA.

ABSTRACT
Reduced Paired box 5 (PAX5) levels have important roles in the pathogenesis of human B-cell acute lymphoblastic leukemia. However, the role of PAX5 in human lymphoma remains unclear. We generated PAX5-silenced cells using mantle cell lymphoma (MCL) as a model system. These PAX5(-) MCL cells exhibited unexpected phenotypes, including increased proliferation in vitro, enhanced tumor infiltration in vivo, robust adhesion to the bone marrow stromal cells and increased retention of quiescent stem-like cells. These phenotypes were attributed to alterations in the expression of genes including p53 and Rb, and to phosphoinositide 3-kinase/mammalian target of rapamycin and phosphorylated signal transducer and activator of transcription 3 pathway hyperactivation. On PAX5 silencing, the MCL cells displayed upregulated interleukin (IL)-6 expression and increased responses to paracrine IL-6. Moreover, decreased PAX5 levels in CD19+ MCL cells correlated with their increased infiltration and progression; thus, PAX5 levels can be used as a prognostic marker independent of cyclin D1 in advanced MCL patients. Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5(-) MCL cells are highly drug-resistant compared with PAX5 wild-type MCL cells. Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B-cell cancer and encourage future efforts to design effective therapies against MCL.

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Related in: MedlinePlus

The roles PAX5 signaling in MCL dissemination and prognosisA model depicting the observations made in this study. MCL patient blood and bone marrow, as well as blastoid MCL samples, displayed significantly lower transcript levels of PAX5. PAX5− Jeko and SP53 MCL cells were generated to emulate this observed PAX5 expression gradient. PAX5− cells exhibited increased proliferation, tumorigenesis, drug resistance, motility and adhesion to the bone marrow microenvironment in vitro and in vivo. PAX5− MCL cells also exhibited elevated phosphorylation of AKT, mTOR, ERK and p38 MAPK.
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Figure 7: The roles PAX5 signaling in MCL dissemination and prognosisA model depicting the observations made in this study. MCL patient blood and bone marrow, as well as blastoid MCL samples, displayed significantly lower transcript levels of PAX5. PAX5− Jeko and SP53 MCL cells were generated to emulate this observed PAX5 expression gradient. PAX5− cells exhibited increased proliferation, tumorigenesis, drug resistance, motility and adhesion to the bone marrow microenvironment in vitro and in vivo. PAX5− MCL cells also exhibited elevated phosphorylation of AKT, mTOR, ERK and p38 MAPK.


Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1.

Teo AE, Chen Z, Miranda RN, McDonnell T, Medeiros LJ, McCarty N - Leukemia (2015)

The roles PAX5 signaling in MCL dissemination and prognosisA model depicting the observations made in this study. MCL patient blood and bone marrow, as well as blastoid MCL samples, displayed significantly lower transcript levels of PAX5. PAX5− Jeko and SP53 MCL cells were generated to emulate this observed PAX5 expression gradient. PAX5− cells exhibited increased proliferation, tumorigenesis, drug resistance, motility and adhesion to the bone marrow microenvironment in vitro and in vivo. PAX5− MCL cells also exhibited elevated phosphorylation of AKT, mTOR, ERK and p38 MAPK.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644730&req=5

Figure 7: The roles PAX5 signaling in MCL dissemination and prognosisA model depicting the observations made in this study. MCL patient blood and bone marrow, as well as blastoid MCL samples, displayed significantly lower transcript levels of PAX5. PAX5− Jeko and SP53 MCL cells were generated to emulate this observed PAX5 expression gradient. PAX5− cells exhibited increased proliferation, tumorigenesis, drug resistance, motility and adhesion to the bone marrow microenvironment in vitro and in vivo. PAX5− MCL cells also exhibited elevated phosphorylation of AKT, mTOR, ERK and p38 MAPK.
Bottom Line: On PAX5 silencing, the MCL cells displayed upregulated interleukin (IL)-6 expression and increased responses to paracrine IL-6.Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5(-) MCL cells are highly drug-resistant compared with PAX5 wild-type MCL cells.Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B-cell cancer and encourage future efforts to design effective therapies against MCL.

View Article: PubMed Central - PubMed

Affiliation: Center for Stem Cell and Regenerative Medicine, Brown Foundation, Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, TX, USA.

ABSTRACT
Reduced Paired box 5 (PAX5) levels have important roles in the pathogenesis of human B-cell acute lymphoblastic leukemia. However, the role of PAX5 in human lymphoma remains unclear. We generated PAX5-silenced cells using mantle cell lymphoma (MCL) as a model system. These PAX5(-) MCL cells exhibited unexpected phenotypes, including increased proliferation in vitro, enhanced tumor infiltration in vivo, robust adhesion to the bone marrow stromal cells and increased retention of quiescent stem-like cells. These phenotypes were attributed to alterations in the expression of genes including p53 and Rb, and to phosphoinositide 3-kinase/mammalian target of rapamycin and phosphorylated signal transducer and activator of transcription 3 pathway hyperactivation. On PAX5 silencing, the MCL cells displayed upregulated interleukin (IL)-6 expression and increased responses to paracrine IL-6. Moreover, decreased PAX5 levels in CD19+ MCL cells correlated with their increased infiltration and progression; thus, PAX5 levels can be used as a prognostic marker independent of cyclin D1 in advanced MCL patients. Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5(-) MCL cells are highly drug-resistant compared with PAX5 wild-type MCL cells. Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B-cell cancer and encourage future efforts to design effective therapies against MCL.

Show MeSH
Related in: MedlinePlus