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Chronic myeloid leukaemia stem cells present an aberrant gene expression signature that is not affected by tyrosine kinase inhibitors

ABSTRACT: Chronic myeloid leukaemia stem cells present an aberrant gene expression signature that is not affected by tyrosine kinase inhibitors

PROVIDER: PRJNA816056 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18324400_1.fastq.gz	Fastqsanger.gz
	SRR18324400_2.fastq.gz	Fastqsanger.gz
	SRR18324401_1.fastq.gz	Fastqsanger.gz
	SRR18324401_2.fastq.gz	Fastqsanger.gz
	SRR18324402_1.fastq.gz	Fastqsanger.gz

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Chronic myeloid leukaemia stem cells present an aberrant gene expression signature that is not affected by tyrosine kinase inhibitors

Project description:Tyrosine kinase inhibitors (TKI) revolutionised the treatment of CML at the beginning of the century. However, TKI do not eliminate the leukaemia stem cells, which can reinitiate the disease upon treatment withdrawal. Thus, finding new therapeutic targets in CML stem cells is key to find a curative treatment. Using microarray datasets, we defined a list of 227 genes which were differentially expressed in CML stem cells compared to healthy controls but were not affected by TKI. Two of them, CD33 and PPIF, are targeted by gemtuzumab-ozogamicin and cyclosporin A, respectively. We treated CML and control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI independent gene expression signature. Cyclosporine A in combination with imatinib reduced the number of CML CFC compared with non-CML controls, but at concentrations not achievable in the clinical practice. Gemtuzumab-ozogamicin showed a EC50 of 146ng/mL, well below the plasma peak concentration of 630ng/mL observed in AML patients and below the EC50 of 3247ng/mL observed in non-CML cells. Interestingly, gemtuzumab-ozogamicin seems to promote cell cycle progression in CML CD34+ cells and we found it to activate the RUNX1 pathway in a RNAseq experiment. This suggests that targeting the tyrosine kinase inhibitor independent gene expression signature in CML stem cells could be exploited for the development of new therapies in CML.

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Phosphoproteomic profiling of Acute Myeloid Leukaemia

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Locking CBL in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukaemia (part2)

Project description:Casitas B-lineage lymphoma (CBL) is critical to the negative regulation of receptor protein tyrosine kinases (RTKs). Mutant CBL can act as an adaptor and gain function to cause myeloproliferative diseases. Currently, there is no beneficial treatment available for leukaemia patients with CBL mutations. Using phage-display technique, we identified a peptide inhibitor CBLock that binds a pocket in CBL’s tyrosine kinase binding domain (TKBD) in its native conformation as revealed by a crystal structure. CBLock inhibits proliferation, causes cell cycle arrest and apoptosis in leukaemia cells that harbour CBL mutations. CBLock disrupts the interaction between CBL mutants and RTK/adaptor protein, hindering the gain-of-function of CBL mutants. We find reduced tumour progression and improved survival upon conditional expression of CBLock in a xenograft AML model. CBLock also resulted in reduced FLT3 downstream signalling. Therefore, inhibiting CBL-TKBD in its native state presents a useful therapeutic opportunity in targeting mutant/inactive CBL-dependent leukaemia.

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Locking CBL in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukaemia (part 1)

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Ibrutinib induces a global chromatin reorganisation in chronic lymphocytic leukaemia

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Expanding the transcriptomic sequence space in leukaemia by RUNX1/RUNX1T1-mediated alternative splicing

Project description:The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukaemia. In this study we comprehensively identify and characterize splicing events associated with RUNX1/RUNX1T1. We show that this oncogene is a regulator of the alternative RNA splicing in leukaemic cells. We found two principal mechanisms underlying changes in the production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start sites selection, and (ii) direct or indirect control of the expression of the genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5’-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals a novel layer of transcriptome re-organization in leukaemia by an aberrant transcriptional regulator.

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Tyrosine Kinase Inhibitor Cardiotoxicity

Project description:Tyrosine Kinase Inhibitor Cardiotoxicity

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Chromatin structure analysis for two patients on Ibrutinib and showing disease progression in chronic lymphocytic leukaemia

Project description:Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in developed countries. Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) represents a major step forward in the treatment of CLL, but cases of resistance are emerging. We have undertaken a detailed analysis of the changes happening to the chromatin structure in CLL cells from two patients on ibrutinib and showing disease progression. ChIP-seq has been performed for H3K4me3, H3K27ac and H3K27me3. We observed chromatin alterations independent of the disease progression. Raw data is available in EGA under controlled access with accession EGAD00001005220

2020-09-01 | E-MTAB-8220 | biostudies-arrayexpress

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