Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Chougule, Rohit A.; Shah, Kinjal; Moharram, Sausan A.; Vallon‐Christersson, Johan; Kazi, Julhash U.

doi:10.1038/s41525-019-0082-y

Cited by 19 publications

(22 citation statements)

References 31 publications

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“…Notably, the analyses with primary B-ALL samples in our study, which revealed a potent induction of NK cell ADCC by 4G8-SDIE, included several CD20 negative cases. This provides further evidence for the value of FLT3 targeting in B-ALL, in particular since other investigators implicated FLT3 to be expressed on leukemic stem cells in ALL [32] and that FLT3 may associate with B-ALL cell resistance to conventional therapy [33]. Heterogeneous expression of FLT3 on the mRNA level and on the cell surface in B-ALL patients has been reported by other investigators [34][35][36], and a trend for a correlation of low FLT3 expression and relapse was observed in an Indian cohort of ALL patients, without reaching statistical significance [34].…”

Section: Discussionsupporting

confidence: 53%

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

Schmied¹,

Lutz²,

Riegg³

et al. 2019

Cancers

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Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to induce NK cell ADCC against B-cell acute lymphoblastic leukemia (B-ALL) by Fc-optimized FLT3 antibody treatment. Flow cytometric analysis confirmed that FLT3 is widely expressed on B-ALL cell lines and leukemic cells of B-ALL patients. FLT3 expression did not correlate with that of CD20, which is targeted by Rituximab, a therapeutic monoclonal antibody (mAb) employed in B-ALL treatment regimens. Our FLT3 mAb with enhanced affinity to the Fc receptor CD16a termed 4G8-SDIE potently induced NK cell reactivity against FLT3-transfectants, the B-ALL cell line SEM and primary leukemic cells of adult B-ALL patients in a target-antigen dependent manner as revealed by analyses of NK cell activation and degranulation. This was mirrored by potent 4G8-SDIE mediated NK cell ADCC in experiments with FLT3-transfectants, the cell line SEM and primary cells as target cells. Taken together, the findings presented in this study provide evidence that 4G8-SDIE may be a promising agent for the treatment of B-ALL, particularly in CD20-negative cases.

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Section: Discussionsupporting

confidence: 53%

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

Schmied¹,

Lutz²,

Riegg³

et al. 2019

Cancers

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“…5f ) were downregulated in TANOUE cells. Although we observed that FLT3 expression was downregulated in predicted dexamethasone-resistant ALL patient samples, in vitro development of dexamethasone resistance in cell lines using long-term culture retained FLT3 expression in resistant cells and even selected for oncogenic FLT3 mutations 5 . Therefore, it is likely that the loss of FLT3 expression occurs in a portion of ALL patients and might not be a common feature for all dexamethasone-resistant ALL samples.…”

Section: Resultsmentioning

confidence: 55%

“…To understand why the model failed to detect two samples as resistant, we analyzed the gene expression data (FPKM) from those samples. In this dataset, three sensitive cell lines (697, NALM6, and RS4;11) were treated with dexamethasone to generate dexamethasone-resistant cell lines 5 . The resistant cell line TANOUE was used as a control and was also treated with dexamethasone for the same period.…”

Section: Resultsmentioning

confidence: 99%

“…Sensitivity to glucocorticoids serves as a positive prognostic indicator, and patients unresponsive to glucocorticoids often relapse, which leads to poor prognosis. Multiple mechanisms of glucocorticoid resistance have been identified such as alterations in expression and function of GR or of GR-associated proteins like chaperones and co-chaperones, thereby affecting their function, and causing defects in the target genes, leading to the inhibition of apoptosis and defective metabolism, cross-talk with other cell signaling pathways and transcription factors, as well as changes in chromatin accessibility 2 – 5 .…”

Section: Introductionmentioning

confidence: 99%

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The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

2021

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Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene signature to develop a deep learning model that can predict dexamethasone sensitivity. By combining gene expression data from cell lines and patients with acute lymphoblastic leukemia, we observed that the model is useful for the classification of patients. Predicted samples have been used to detect deregulated pathways that lead to dexamethasone resistance. Gene set enrichment analysis, peptide substrate-based kinase profiling assay, and western blot analysis identified Aurora kinase, S6K, p38, and β-catenin as key signaling proteins involved in dexamethasone resistance. Deep learning-enabled drug synergy prediction followed by in vitro drug synergy analysis identified kinase inhibitors against Aurora kinase, JAK, S6K, and mTOR that displayed synergy with dexamethasone. Combining pathway enrichment, kinase regulation, and kinase inhibition data, we propose that Aurora kinase or its several direct or indirect downstream kinase effectors such as mTOR, S6K, p38, and JAK may be involved in β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β. Collectively, our data suggest that activation of the Aurora kinase/β-catenin axis during dexamethasone treatment may contribute to cell survival signaling which is possibly maintained in patients who are resistant to dexamethasone.

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“…Currently, glucocorticoids (GCs), such as prednisone and dexamethasone, in combination with conventional chemotherapeutic agents such as cytarabine, etoposide, or daunorubicin are used to treat infant ALL. Although GC is a key agent for targeting lymphoid malignancies, basic experimental studies showed that MLL-ALL cells become rapidly resistant to GCs in vitro [ [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] ] an in vivo [ 3 , 18 , 20 , 21 ]. Therefore, it is important to develop new drugs that can recognize the abnormal proteins, expressed by MLL-ALL cells and subsequently eliminate these.…”

Section: Introductionmentioning

confidence: 99%

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia

et al. 2021

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Background Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. Methods Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. Findings Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. Interpretation SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. Funding This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.

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Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Cited by 19 publications

References 31 publications

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody

The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia

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