ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Abstract

Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and post-injury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from chronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.

ANP32B suppresses B‐cell acute lymphoblastic leukemia through activation of PU.1 in mice

“…The roles of ANP32B in tumorigenesis are due to its cellular and genetic context. Although ANP32B has been reported to serve as a tumor-promoting gene in breast cancer and CML, 23,24 41,42 so the underlying mechanisms of down-regulation of ANP32B in B-ALL patients need to be further studied.…”

“…In addition, tumorbearing mice also had enlarged lymph nodes and exhibited hepatosplenomegaly (Figure S1F,G). B220 + BM cells of tamoxifen treated Scl-Cre − ; Anp32b fl/fl and Scl-Cre + ; Anp32b fl/fl mice, which we previously reported and referred to as Anp32b +/+ and Anp32b −/− mice, 24 were infected with N-myc-GFP retrovirus and then transplanted into lethally irradiated recipients.…”

“…Our recent study reveals that ANP32B interacts with p53 to regulate hematopoiesis and CML leukemogenesis. 24 To determine whether ANP32B inhibits B-ALL development through regulating p53 activity, we used Anp32b +/+ p53 +/+ , Anp32b +/+ p53 +/− , Anp32b −/− p53 +/+ , and Anp32b −/− p53 +/− mice in our pervious study to induce B-ALL. Survival analysis showed that although heterozygous p53 loss in Anp32b +/+ cells accelerated BCR-ABL p190 -induced leukemogenesis, Anp32b −/− p53 +/− mice presented similar survival compared with Anp32b −/− p53 +/+ mice (Figure S3B), suggesting that ETS (DNA-binding domain) of PU.1 is essential for its interaction with ANP32B (Figure 4E).…”

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia

“…Immunoprecipitation of Flag-tagged proteins or endogenous proteins and Nano-LC-MS/MS with electrospray ionization used to identify interacting proteins were performed as previously described [ 28 , 29 ]. The antibodies used in immunoprecipitation are listed in Additional file 1 : Table S1.…”

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

“…Single-cell analysis reveals two distinct subsets of BCR-ABL + stem cells from patients who achieved hematological remission after being subjected to TKI treatments, with one group enriched for a quiescent gene signature and the other enriched for MYC and proliferation-associated gene sets, suggesting clonally segregated CML LSCs may account for differential sensitivities to TKIs, which can impact treatment outcomes [ 168 ]. Furthermore, transcriptomic profiling has revealed many signaling pathways integral for CML LSC survival, including the TP53-cMYC signaling network [ 169 , 170 ], arachidonate 5-lipoxygenase ( Alox5 ) [ 171 ], tyrosine-protein kinase BLK [ 172 ], the NFκB pathway [ 173 ], the JAK2/STAT5 axis [ 174 , 175 ], the AHI-BCR-ABL-JAK2-DNM2 network [ 176 , 177 ], Wnt activation [ 178 ], the proinflammatory transforming growth factor (TGF)-β and tumor-necrosis factor (TNF)-α signaling pathways [ 179 ], and integrin-linked kinase signaling [ 180 ]. Of note, CML LSCs, in comparison to their normal counterparts, can generate alternative transcript isoforms for genes, particularly those involved in the cellular proliferation and p53 signaling pathways [ 181 ].…”