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Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside.

ABSTRACT: While the underlying genetic alterations and biology of acute myeloid leukemia (AML), an aggressive hematologic malignancy characterized by clonal expansion of undifferentiated myeloid cells, have been gradually unraveled in the last decades, translation into clinical treatment approaches has only just begun. High relapse rates remain a major challenge in AML therapy and are to a large extent attributed to the persistence of treatment-resistant leukemic stem cells (LSCs). The Hedgehog (HH) signaling pathway is crucial for the development and progression of multiple cancer stem cell driven tumors, including AML, and has therefore gained interest as a therapeutic target. In this review, we give an overview of the major components of the HH signaling pathway, dissect HH functions in normal and malignant hematopoiesis, and specifically elaborate on the role of HH signaling in AML pathogenesis and resistance. Furthermore, we summarize preclinical and clinical HH inhibitor studies, leading to the approval of the HH pathway inhibitor glasdegib, in combination with low-dose cytarabine, for AML treatment.

SUBMITTER: Tesanovic S

PROVIDER: S-EPMC9388743 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside.

Tesanovic Suzana S Krenn Peter W PW Aberger Fritz F

Frontiers in cell and developmental biology 20220805

While the underlying genetic alterations and biology of acute myeloid leukemia (AML), an aggressive hematologic malignancy characterized by clonal expansion of undifferentiated myeloid cells, have been gradually unraveled in the last decades, translation into clinical treatment approaches has only just begun. High relapse rates remain a major challenge in AML therapy and are to a large extent attributed to the persistence of treatment-resistant leukemic stem cells (LSCs). The Hedgehog (HH) signa ...[more]

PMID: 35990601

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Project description:The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.

Dataset Information

Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside.

Publications

Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside.

Similar Datasets

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