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LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms

ABSTRACT: LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms

PROVIDER: PRJNA864834 | ENA |

REPOSITORIES: ENA

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LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms

Project description:The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs.

2022-08-01 | GSE210253 | GEO

LKB1/STK11 is a tumor suppressor in the leukemic transformation of myeloproliferative neoplasms

Project description:LKB1/STK11 is a tumor suppressor in the leukemic transformation of myeloproliferative neoplasms

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Myelodysplastic/myeloproliferative neoplasms

Project description:This SuperSeries is composed of the following subset Series: GSE21948: High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms GSE21990: Affymetrix SNP 6.0 array data for myelodysplastic/myeloproliferative neoplasms Refer to individual Series

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AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

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LKB1/<i>STK11</i> Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.

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LKB1/STK11 Inactivation Leads to Expansion of Pro-Metastatic Tumor Sub-Population in Melanoma

Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population reference x sample

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Transcription profile of WT and LKB1 (encoded by the gene Stk11)-deficient Treg cells

Project description:LKB1 deficiency in Treg cells impairs their survival, metabolism and suppressive function. To exclude the impact of excessive inflammation on LKB1-deficient Treg cells, we generated mixed bone marrow (BM) chimeras using Foxp3-Cre WT and Foxp3-Cre Stk11 fl/fl BM cells, together with CD45.1+ BM cells. We used microarray to compare the global transcription profile of dornor-derived LKB1-deficient Tregs with WT counterparts.

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Gene expression profiling of mouse MPN cells with or without STK11 knockout

Project description:We performed RNA-sequencing of mouse cells derived from colony forming assays (CFA) to evaluate the transcriptome of MPN cells with deletion of the tumor suppressor STK11/LKB1 and relative controls. The CFA are from mouse primary floxed STK11 hematopoietic stem and progenitor cells (HSPCs) transduced with retroviruses encoding the MPN mutation MPLW515L and CRE recombinase to delete STK11.

2021-01-27 | GSE159737 | GEO

Pathophysiology of arterial cardiovascular events in patients with JAK2V617F myeloproliferative neoplasms

Project description:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.

2020-02-17 | PXD014451 | Pride

Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

Project description:Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

2023-05-24 | GSE229712 | GEO