<i>LCK</i>over-expression drives STAT5 oncogenic signaling in<i>PAX5</i>translocated BCP-ALL patients

Cazzaniga, Valeria; Bugarin, Cristina; Bardini, Michela; Giordan, Marco; Kronnie, Geertruy te; Basso, Giuseppe; Biondi, Andrea; Fazio, Grazia; Cazzaniga, Giovanni

doi:10.18632/oncotarget.2807

Cited by 18 publications

(26 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is similar to what has been described for PCP-ALL cells, where a PAX5 fusion protein drives overexpression of LCK. In those cells, there is an LCK-dependent hyperphosphorylation of STAT5 42 . Similar to in vitro colony formation data, mice injected with cells expressing LCK and FLT3-ITD developed tumors quicker than cells lacking LCK expression.…”

Section: Discussionmentioning

confidence: 99%

The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation

Marhäll

Kazi

2017

Sci Rep

View full text Add to dashboard Cite

The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector. Staining of the tissues from mouse xenografts showed higher Ki67 staining in cells expressing LCK suggesting that expression of LCK enhances the FLT3-ITD-mediated proliferative capacity. LCK expression did not affect either FLT3-WT or FLT3-ITD -induced AKT, ERK1/2 or p38 phosphorylation. However, LCK expression significantly enhanced FLT3-ITD-mediated STAT5 phosphorylation. Taken together, our data suggest that LCK cooperates with oncogenic FLT3-ITD in cellular transformation.

show abstract

Section: Discussionmentioning

confidence: 99%

The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation

Marhäll

Kazi

2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…[18][19][20] The triple angiokinase inhibitor nintedanib was recently clinically approved for idiopathic pulmonary fibrosis treatment and targets LCK. 21,22 WH-4-023 is a high-specific and orally active LCK inhibitor. 23 For 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) and apoptosis tests, they were used at the specified concentrations alone or in combination with dexamethasone (Dex; Sigma-Aldrich).…”

Section: In Vitro Treatmentsmentioning

confidence: 99%

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Serafin¹,

Capuzzo²,

Milani³

et al. 2017

Blood

Self Cite

View full text Add to dashboard Cite

Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 () overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients.

show abstract

“…Values are expressed as mean values of MFI log 2 ratio (inhibited/basal state) for p4EBP1 (a), pAkt473 (b), and pS6 (c). BEZ abrogates phosphorylation below basal levels regardless of PTEN status different cellular subsets (Cazzaniga et al, 2015;Hasegawa et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

Single‐cell profiling of pediatric T‐cell acute lymphoblastic leukemia: Impact of PTEN exon 7 mutation on PI3K/Akt and JAK–STAT signaling pathways

Bonaccorso

Bugarin

Buracchi

et al. 2020

Cytometry Part B Clinical

Self Cite

View full text Add to dashboard Cite

Background: The PI3K/Akt/mTOR (PI3K) signaling pathway has a crucial role in T-cell acute lymphoblastic leukemias (T-ALLs). Although loss-of-function of phosphatase and tensin homolog (PTEN) is a common event in pediatric T-ALLs, the exact role of this tumor suppressor in TALL development has yet to be defined. Methods: Here, we report an optimized cytometric method for accurate proteomic profiling of TALL leukemic blasts at single-cell level. We determined the expression of PI3K and JAK-STAT signaling components in both primary and immortalized TALL cells as well as in normal T cells. Results: We observed that PTEN exon 7 mutated TALL cells retain a distinct PI3K activation; in particular, these cells show higher pAkt levels and a lower pS6 expression. Interestingly, we demonstrated for the first time that PTEN exon 7 mutated TALL are nonresponsive to IL7 in vitro as assessed by lack of pSTAT5 activation, although they do express IL7R. Conclusions: Phosphoflow analysis represents a fast, reliable, and accurate method to study the signaling profile of TALL. PTEN exon 7 mutated TALL cells are nonresponsive to IL7 in vitro suggesting that they may activate other mechanisms to support their viability and proliferation such as a higher constitutive PI3K/Akt signaling. Further investigations are necessary to elucidate the significance of this peculiar signaling behavior. Our observations should be taken into account in future studies aiming at molecular targeting of PI3K and/or JAK/STAT pathways for pharmacological intervention in TALL .

show abstract

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

Cited by 18 publications

References 37 publications

The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation

The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

Single‐cell profiling of pediatric T‐cell acute lymphoblastic leukemia: Impact of PTEN exon 7 mutation on PI3K/Akt and JAK–STAT signaling pathways

Contact Info

Product

Resources

About