Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity

Bonnie W. Lau; Kyounghee Huh; Rafael Madero-Marroquin; Federico De Marchi; Yiting Lim; Qiuju Wang; Francisco Lobo; Luigi Marchionni; Douglas B. Smith; Amy DeZern; Mark J. Levis; Peter D. Aplan; William Matsui; Lukasz P. Gondek

doi:10.1038/s41388-018-0431-9

Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity

Bonnie W. Lau, Kyounghee Huh, Rafael Madero-Marroquin, Federico De Marchi, Yiting Lim, Qiuju Wang, Francisco Lobo, Luigi Marchionni, Douglas B. Smith, Amy DeZern, Mark J. Levis, Peter D. Aplan, William Matsui, Lukasz P. Gondek

School of Medicine

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

Original language	English (US)
Pages (from-to)	687-698
Number of pages	12
Journal	Oncogene
Volume	38
Issue number	5
DOIs	https://doi.org/10.1038/s41388-018-0431-9
State	Published - Jan 31 2019

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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Lau, B. W., Huh, K., Madero-Marroquin, R., De Marchi, F., Lim, Y., Wang, Q., Lobo, F., Marchionni, L., Smith, D. B., DeZern, A., Levis, M. J., Aplan, P. D., Matsui, W., & Gondek, L. P. (2019). Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity. Oncogene, 38(5), 687-698. https://doi.org/10.1038/s41388-018-0431-9

Lau, BW, Huh, K, Madero-Marroquin, R, De Marchi, F, Lim, Y, Wang, Q, Lobo, F, Marchionni, L, Smith, DB , DeZern, A , Levis, MJ, Aplan, PD, Matsui, W & Gondek, LP 2019, 'Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity', Oncogene, vol. 38, no. 5, pp. 687-698. https://doi.org/10.1038/s41388-018-0431-9

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title = "Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity",

abstract = "Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.",

author = "Lau, {Bonnie W.} and Kyounghee Huh and Rafael Madero-Marroquin and {De Marchi}, Federico and Yiting Lim and Qiuju Wang and Francisco Lobo and Luigi Marchionni and Smith, {Douglas B.} and Amy DeZern and Levis, {Mark J.} and Aplan, {Peter D.} and William Matsui and Gondek, {Lukasz P.}",

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doi = "10.1038/s41388-018-0431-9",

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T1 - Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity

AU - Lau, Bonnie W.

AU - Huh, Kyounghee

AU - Madero-Marroquin, Rafael

AU - De Marchi, Federico

AU - Lim, Yiting

AU - Wang, Qiuju

AU - Lobo, Francisco

AU - Marchionni, Luigi

AU - Smith, Douglas B.

AU - DeZern, Amy

AU - Levis, Mark J.

AU - Aplan, Peter D.

AU - Matsui, William

AU - Gondek, Lukasz P.

PY - 2019/1/31

Y1 - 2019/1/31

N2 - Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

AB - Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

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Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity

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