The role of STAT5 in the development, function, and transformation of B and T lymphocytes

Heltemes-Harris, Lynn; Willette, Mark; Vang, Kieng B.; Farrar, Michael A.

doi:10.1111/j.1749-6632.2010.05907.x

Cited by 37 publications

(25 citation statements)

References 97 publications

(224 reference statements)

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“…Interestingly, STAT5 over-activation and PAX5 haplo-insufficiency have been described as synergistic players to initiate ALL [28, 32]. In the present study we demonstrated that both these aberrancies are not only necessary to drive leukemia, but they are a direct consequence of the expression of the PAX5 fusion protein, which can a) repress the activity of endogenous PAX5 [11] and b) activate STAT5 through LCK (Figure 6).…”

Section: Discussionsupporting

confidence: 58%

“…Indeed, we demonstrated by phosphoflow analysis that PAX5/ETV6 transduced cells showed increased Stat5 phosphorylation, and the up-regulation of two downstream targets cMyc and Ccnd2 , known to have a role in cell cycle progression and malignant transformation [22, 28, 29]. We also demonstrated that IL7Rα (CD127) was expressed at the same level both in PAX5/ETV6 and MIGR-GFP cells, thus suggesting that increased Stat5 phosphorylation was independent from classical IL7R signaling cascade [21].…”

Section: Discussionmentioning

confidence: 99%

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LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

et al. 2015

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The PAX5 gene is altered in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2–3% of cases. Although PAX5 fusion genes significantly affect the transcription of PAX5 target genes, their role in sustaining leukemia cell survival is poorly understood.In an in vitro model of PAX5/ETV6 leukemia, we demonstrated that Lck hyper-activation, and down-regulation of its negative regulator Csk, lead to STAT5 hyper-activation and consequently to the up-regulation of the downstream effectors, cMyc and Ccnd2. More important, cells from PAX5 translocated patients show LCK up-regulation and over-activation, as well as STAT5 hyper-phosphorylation, compared to PAX5 wt and PAX5 deleted cases. As in BCR/ABL1 positive ALL, the hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells, alternative to the pre-BCR, which is down-regulated. The LCK inhibitor BIBF1120 selectively reverts this phenomenon both in the murine model and in leukemic primary cells. LCK inhibitor could therefore represent a suitable candidate drug to target this subgroup of ALL patients.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

et al. 2015

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“…It has been found aberrantly activated in leukemia and lymphoma as well as solid cancers as breast and prostate cancer (reviewed in refs. [43][44][45]. In this light, it is surprising how little is known about the function of STAT5 and its downstream targets in CTCL.…”

Section: Discussionmentioning

confidence: 99%

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

et al. 2013

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“…Deregulated Stat5 activity in the hematopoietic system is associated with the development of Hodgkin's lymphoma and Burkett's lymphoma in humans [19] and, via the kinase BCR–ABL, with myeloid leukemia [20]. In the mammary gland, studies in transgenic animal models have indicated that deregulated STAT5 levels and activity represent a genuine risk factor for breast cancer [21].…”

Section: Introductionmentioning

confidence: 99%

Luminal STAT5 mediates H2AX promoter activity in distinct population of basal mammary epithelial cells

et al. 2016

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Deregulated STAT5 activity in the mammary gland causes parity-dependent tumorigenesis. Epithelial cell cultures transfected with constitutively active STAT5 express higher levels of the histone H2AX than their non-transfected counterparts. Higher H2AX expression may be involved in tumorigenesis. Here, we aimed to link high STAT5 activity to H2AX–GFP expression by looking for distinct types of mammary cells that express these proteins. In vitro and in transgenic mice, only 0.2 and 0.02%, respectively, of the cells expressed the H2AX–GFP hybrid gene. Its expression correlated with that of the endogenous H2AX gene, suggesting that detectable H2AX–GFP expression marks high levels of H2AX transcript. Methylation of the H2AX promoter characterized non-GFP-expressing H2AX–GFP cells and was inversely correlated with promoter activity. Administration of 5-azacytidine increased H2AX promoter activity in an activated STAT5-dependent manner. In transgenic mice, H2AX–GFP expression peaked at pregnancy. The number of H2AX–GFP-expressing cells and GFP expression decreased in a Stat5a-null background and increased in mice expressing the hyperactivated STAT5. Importantly, H2AX–GFP activity was allocated to basal mammary cells lacking stem-cell properties, whereas STAT5 hyperactivity was detected in the adjacent luminal cells. Knockdown of RANKL by siRNA suggested its involvement in signaling between the two layers. These results suggest paracrine activation of H2AX via promoter demethylation in specific populations of basal mammary cells that is induced by a signal from neighboring luminal cells with hyper STAT5 activity. This pathway provides an alternative route for the luminally confined STAT5 to affect basal mammary cell activity.

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The role of STAT5 in the development, function, and transformation of B and T lymphocytes

Cited by 37 publications

References 97 publications

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

Luminal STAT5 mediates H2AX promoter activity in distinct population of basal mammary epithelial cells

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