hes1-protein--human and Blast-Crisis

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blast Crisis; Genes, abl; Hematopoietic Stem Cells; Homeodomain Proteins; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Molecular Targeted Therapy; Transcription Factor HES-1

We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-α (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRα alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFRα developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRα conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1-PDGFRα, but not with imatinib-resistant FIP1L1-PDGFRα mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRΑ mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.

Topics: Amino Acid Substitution; Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Benzamides; Blast Crisis; Female; Gene Expression Regulation, Leukemic; Homeodomain Proteins; Humans; Imatinib Mesylate; Interleukin-3; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred BALB C; mRNA Cleavage and Polyadenylation Factors; Mutation, Missense; Neoplasms, Experimental; Oncogene Proteins, Fusion; Piperazines; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Transcription Factor HES-1

High levels of HES1 expression are frequently found in BCR-ABL(+) chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however, the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-κB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, CMPs expressing BCR-ABL and Hes1 secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. The present results suggest that Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blast Crisis; Bone Marrow Transplantation; Cell Movement; Cell Proliferation; Flow Cytometry; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Homeodomain Proteins; Humans; Kaplan-Meier Estimate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Matrix Metalloproteinase 9; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Models, Genetic; NF-kappa B; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcription Factor HES-1; Up-Regulation

Hairy enhancer of split 1 (Hes1) is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Here we show that retroviral expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the presence of interleukin-3, conferring permanent replating capability on these cells. Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered to irradiated mice, the combination of Hes1 and BCR-ABL in CMPs and GMPs caused acute leukemia resembling blast crisis of chronic myelogenous leukemia (CML), resulting in rapid death of the recipient mice. On the other hand, BCR-ABL alone caused CML-like disease when expressed in c-Kit-positive, Sca-1-positive, and lineage-negative hematopoietic stem cells (KSLs), but not committed progenitors CMPs or GMPs, as previously reported. Leukemic cells derived from Hes1 and BCR-ABL-expressing CMPs and GMPs were more immature than those derived from BCR-ABL-expressing KSLs. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results suggest that Hes1 is a key molecule in blast crisis transition in CML.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blast Crisis; Cell Line, Transformed; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Progenitor Cells; Homeodomain Proteins; Interleukin-3; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Neoplastic Stem Cells; Rats; Repressor Proteins; Transcription Factor HES-1