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The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

ABSTRACT: Oncogene driven transformation of leukemic progenitors results in B-acute lymphoblastic leukemia. Genetic deletions at specific hotspots are driven by recombination of epigenetically repressed loci and cause B cell transformation, and epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. The upstream signals driving epigenetic silencing have not been elucidated. BCR-ABL leukemias are initiated by leukemic stem cells/progenitors, and their modeling in vivo represents an opportunity for the identification of the epigenetic progress contributing to lineage leukemogenesis. We have found that primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCz behaves as a leukemic suppressor, aPKCl/i is critically required for oncogenic progenitor proliferation, survival, and B cell differentiation arrest, but not for normal B cell lineage differentiation. We found that in vitro and in vivo B cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKCl/i-dependent Etv5/Satb2 chromatin repressive signaling complex. Thus genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias in vitro and in vivo. Therefore, the aPKCl/i-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-BCR-ABL kinase inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE121018 | GEO | 2018/10/10

REPOSITORIES: GEO

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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.

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The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

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