Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia

HALT Pan-Leukemia Gene Panel Consortium

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

Original languageEnglish (US)
Pages (from-to)2651-2663
Number of pages13
JournalBlood
Volume133
Issue number25
DOIs
StatePublished - Jun 20 2019

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B-Cell Chronic Lymphocytic Leukemia
Disease Progression
Chemical activation
Patient treatment
Gene encoding
Genes
Association reactions
Mutation
Molecules
Leukemia
Proteins
Survival
Therapeutics
GANT 61

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia. / HALT Pan-Leukemia Gene Panel Consortium.

In: Blood, Vol. 133, No. 25, 20.06.2019, p. 2651-2663.

Research output: Contribution to journalArticle

HALT Pan-Leukemia Gene Panel Consortium. / Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia. In: Blood. 2019 ; Vol. 133, No. 25. pp. 2651-2663.
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abstract = "Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11{\%}) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38{\%} of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.",
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AU - Yousif, Fouad

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AU - Mcpherson, John Douglas

AU - Hudson, Thomas J.

AU - Harismendy, Olivier

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AU - Kipps, Thomas J.

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