Dataset Information

Deletion of miR-15a/16-1 in murine germinal center B-cells.

ABSTRACT: Given the tumor suppressing function of miR-15a/16-1 cluster, we studied its role in the germinal center B-cells that give rise to most lymphoid malignancies.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Lymph Node

DISEASE(S): Acute Leukemia

SUBMITTER: Tomasz Sewastianik

LAB HEAD: Ruben D. Carrasco

PROVIDER: PXD021323 | Pride | 2021-09-09

REPOSITORIES: Pride

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Publications

miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms.

Sewastianik Tomasz T Straubhaar Juerg R JR Zhao Jian-Jun JJ Samur Mehmet K MK Adler Keith K Tanton Helen E HE Shanmugam Vignesh V Nadeem Omar O Dennis Peter S PS Pillai Vinodh V Wang Jianli J Jiang Meng M Lin Jianhong J Huang Ying Y Brooks Daniel D Bouxsein Mary M Dorfman David M DM Pinkus Geraldine S GS Robbiani Davide F DF Ghobrial Irene M IM Budnik Bogdan B Jarolim Petr P Munshi Nikhil C NC Anderson Kenneth C KC Carrasco Ruben D RD

Blood 20210401 14

Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. W ...[more]

PMID: 33751108

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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.

Dataset Information

Deletion of miR-15a/16-1 in murine germinal center B-cells.

Publications

miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms.

Similar Datasets

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