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Lenalidomide-mediated erythroid improvement in non-del(5q) myelodysplastic syndromes is associated with bone marrow immuno-remodeling [Affymetrix]

ABSTRACT: In the field of MDS and on bone marrow mononuclear cells , we search for a signature which predict the response to Lenalidomide treatment. This transcriptome study appended to the GFM-LEN-EPO-2008 clinical trial reports a predictive signature of response to lenalidomide and a unique immune response signature after treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102976 | GEO | 2017/08/24

REPOSITORIES: GEO

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Differential response to Lenalidomide from WT and RUNX1-KO MDS-L del(5q) cells

Project description:We used CRISPR/Cas9 system to generate WT Control and RUNX1-KO MDS-L cells isolated as single clones from the parental MDS-L cell line. We have observed that RUNX1-KO MDS-L cells are resistant to Lenalidomide-induced cell death compared to WT Control MDS-L cells We have treated WT and RUNX1-KO MDS-L cells with 1µM Lenalidomide for 24h or 72h and performed expression analysis

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Lenalidomide Resistance in del(5q) Myelodysplastic Syndrome Follows Loss of RUNX1/TP53-mediated Megakaryocytic Differentiation

Project description:Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN

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Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) Myelodysplastic Syndromes and impact of lenalidomide

Project description:While del(5q) MDS patients comprise a well-defined hematological subgroup, the molecular basis underlying its origin and the reason behind the relapse to lenalidomide remains unknown. Using scRNAseq on CD34+ progenitor cells from patients with del(5q) MDS we were able to identify cells harboring the deletion, enabling us to deeply characterize the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. We found, across all patients, an enrichment of del(5q) cells in GMP and megakaryocyte-erythroid progenitors not described to date. Interestingly, both del(5q) and non-del(5q) cells presented similar transcriptional lesions when compared to progenitors from healthy individuals, indicating that all cells, and not only those harboring the deletion, are altered in these patients and may contribute to aberrant hematopoietic differentiation. However, GRN analysis revealed a group of regulons with aberrant activity in del(5q) cells that could be responsible for triggering altered hematopoiesis, pointing to a more prominent role of these cells in the phenotype of these patients. An analysis of del(5q) MDS patients achieving hematological response upon lenalidomide treatment showed that the drug reverted several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remained, which may be responsible for potential future relapses. Moreover, lack of hematological response was associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study provides a deep characterization of del(5q) and non-del(5q) cells at single-cell resolution, revealing previously unknown transcriptional alterations that could contribute to disease pathogenesis, or lack of responsiveness to lenalidomide.

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Lenalidomide-mediated erythroid improvement in non-del(5q) myelodysplastic syndromes is associated with bone marrow immuno-remodeling [Affymetrix]

Project description:Lenalidomide-mediated erythroid improvement in non-del(5q) myelodysplastic syndromes is associated with bone marrow immuno-remodeling [Affymetrix]

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A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes

Project description:Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.

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Affymetrix SNP array data for myelodysplastic syndrome with 5q deletion treated with lenalidomide

Project description:Lenalidome is a drug especially effective in low risk myelodysplastic syndromes (MDS) with isolated 5q deletion. However, 25% of the patients did not respond. TP53 mutations have been described to play a role in the disease progression, and karyotypic complexity also has an important impact in the outcome. We selected 53 MDS patients with 5q deletion and treated with lenalidomide and we studied by the following techniques: conventional G-banding cytogenetics (CC), single nucleotide polymorphism arrays (SNP-A) and sequencing, in order to assess their impact on treatment response and disease progression. Low karyotypic complexity (by CC), a high baseline platelet count (>280x103/L) and TP53 unmutated gene status are associated with the achievement of hematological response (P=0.005, P=0.008 and P=0.057, respectively). In a multivariate model, the most important predictors for lenalidomide failure are karyotypic complexity (P=0.014) and a platelet count below 280x103/L (P=0.042). Additionally, none of the TP53 mutated cases achieved complete cytogenetics response. Nevertheless, inclusion of defects by SNP-A did not allow for a better separation of responders and non responders. These findings constitute a useful reference data to be considered before lenalidomide treatment enrollment.

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Differential response to Lenalidomide from WT and RUNX1-KO MDS-L del(5q) cells

Project description:Differential response to Lenalidomide from WT and RUNX1-KO MDS-L del(5q) cells

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Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Project description: Not available

| S-EPMC9208896 | biostudies-literature

Affymetrix SNP array data for myelodysplastic syndrome with 5q deletion treated with lenalidomide

2013-07-01 | E-GEOD-35656 | biostudies-arrayexpress

Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.

Project description:Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

| S-EPMC4853910 | biostudies-literature

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