Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia

Samuels, A. Lacey; Heng, J.; Beesley, Alex H.; Kees, Ursula R.

doi:10.1111/bjh.12727

Cited by 35 publications

(33 citation statements)

References 47 publications

(62 reference statements)

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“…6 In recent years, several efforts have been made to understand the basis of GC resistance in T-ALL. Beesley and colleagues 36,37 reported that GC resistance is directly associated with a glycolytic phenotype, and the hyperactivation of the PI3K/AKT pathway was observed in GC-resistant T-ALL cells. 38 Despite this, precise mechanisms that lead to poor response to GC in T-ALL patients are not yet fully understood.…”

Section: Discussionmentioning

confidence: 99%

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

Serafin¹,

Capuzzo²,

Milani³

et al. 2017

Blood

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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.

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Section: Discussionmentioning

confidence: 99%

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

Serafin¹,

Capuzzo²,

Milani³

et al. 2017

Blood

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“…Consistent with increased glycolysis, PKM2 transcript levels were increased in 2S-stimulated cells (Figure 4a). Inhibition of AKT can be achieved by inhibiting glycolysis with 2-deoxyglucose (2-DG) [28] and sensitizes acute leukemia cells to DEX [29, 30]. 2-DG (3 mM) decreased the size of 2S-stimulated CLL cells and their expression of phospho-AKT and -FOXO1 (Figure 4b, 4c).…”

Section: Resultsmentioning

confidence: 99%

Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells

et al. 2016

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Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.

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“…2‐DG in combination with inhibition of the anti‐apoptotic protein MCL1 can reduce leukemia cell survival and resensitize cALL cells to prednisolone in vitro 92 . Targeting multiple aspects of lymphoblast cell metabolism with 2‐DG, oligomycin, and a cholesterol metabolism inhibitor as single drugs and in combinations including with methylprednisolone can also resensitize cells in vitro to GCs 93 …”

Section: Cell Metabolism In Callmentioning

confidence: 99%

Metabolic reprogramming in childhood acute lymphoblastic leukemia

Sbirkov

Burnusuzov

Sarafian

2020

Pediatric Blood & Cancer

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The first observations of altered metabolism in malignant cells were made nearly 100 years ago and therapeutic strategies targeting cell metabolism have been in clinical use for several decades. In this review, we summarize our current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL). Reprogramming of cellular bioenergetic processes can be expected in the three distinct stages of cALL: at diagnosis, during standard chemotherapy, and in cases of relapse. Upregulation of glycolysis, dependency on anaplerotic energy sources, and activation of the electron transport chain have all been observed in cALL.While the current treatment strategies are tackling some of these aberrations, cALL cells are likely to be able to rewire their metabolism in order to escape therapy, which may contribute to a refractory disease and relapse. Finally, here we focus on novel therapeutic approaches emerging from our evolving understanding of the alterations of different metabolic networks in lymphoblasts. K E Y W O R D SBioenergetics, cALL, cell metabolism, therapy

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Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia

Cited by 35 publications

References 47 publications

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

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

Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells

Metabolic reprogramming in childhood acute lymphoblastic leukemia

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