Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression

Shin Kasai, Yoshiyuki Furuichi, Norie Ando, Keiko Kagami, Masako Abe, Takaya Nakane, Kumiko Goi, Takeshi Inukai, Sei Saitoh, Shinichi Ohno, Shogo Okazaki, Osamu Nagano, Hideyuki Saya, Kanji Sugita

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Acute lymphoblastic leukemia (ALL) with mixed lineage leukemia (MLL) gene rearrangements (MLL+ALL) has a dismal prognosis and is characterized by high surface CD44 expression. Known that CD44 has the specific binding sites for a natural ligand hyaluronan (HA), we investigated biological effects of HA with different molecular sizes on MLL+ALL cell lines, and found that the addition of ultra-low-molecular-weight (ULMW)-HA strongly suppressed their thymidine uptakes. The MLL+ALL cell line lacking surface CD44 expression established by genome editing showed no suppression of thymidine uptake. Surface CD44-high B-precursor ALL cell lines other than MLL+, but not T-ALL cell lines, were also suppressed in their thymidine uptakes. The inhibition of thymidine uptakes was because of induction of cell death, but dead cells lacked features of apoptosis on cytospin smears and flow cytometric analysis. The cell death was neither blocked by pan-caspase inhibitor nor autophagy inhibitor, but was completely blocked by necrosis inhibitor necrostatin-1. Necrotic cell death was further supported by a marked release of a high-mobility protein group B1 and morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production suggested a role for inducing this necrotic cell death. ULMW-HA-triggered cell death was similarly demonstrated in surface CD44-high primary B-precursor leukemia cells. Assuming that ULMW-HA is abundantly secreted at the site of infection and inflammation, this study sheds light on understanding the mechanism of a transient inflammation-associated remission of leukemia. Further, the CD44-targeting may become an effective approach in future for the treatment of refractory B-precursor ALL by its capability of predominantly eradicating CD44-high leukemia-initiating cells.

Original languageEnglish
Pages (from-to)e2857
JournalCell death & disease
Volume8
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

Fingerprint

B-Cell Leukemia
B-Lymphoid Precursor Cells
Hyaluronic Acid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Necrosis
Molecular Weight
Biphenotypic Acute Leukemia
Cell Death
Thymidine
Cell Line
High Mobility Group Proteins
Inflammation
Caspase Inhibitors
Gene Rearrangement
Autophagy
Transmission Electron Microscopy
Reactive Oxygen Species
Binding Sites
Apoptosis

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression. / Kasai, Shin; Furuichi, Yoshiyuki; Ando, Norie; Kagami, Keiko; Abe, Masako; Nakane, Takaya; Goi, Kumiko; Inukai, Takeshi; Saitoh, Sei; Ohno, Shinichi; Okazaki, Shogo; Nagano, Osamu; Saya, Hideyuki; Sugita, Kanji.

In: Cell death & disease, Vol. 8, No. 6, 01.06.2017, p. e2857.

Research output: Contribution to journalArticle

Kasai, S, Furuichi, Y, Ando, N, Kagami, K, Abe, M, Nakane, T, Goi, K, Inukai, T, Saitoh, S, Ohno, S, Okazaki, S, Nagano, O, Saya, H & Sugita, K 2017, 'Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression', Cell death & disease, vol. 8, no. 6, pp. e2857. https://doi.org/10.1038/cddis.2017.249
Kasai, Shin ; Furuichi, Yoshiyuki ; Ando, Norie ; Kagami, Keiko ; Abe, Masako ; Nakane, Takaya ; Goi, Kumiko ; Inukai, Takeshi ; Saitoh, Sei ; Ohno, Shinichi ; Okazaki, Shogo ; Nagano, Osamu ; Saya, Hideyuki ; Sugita, Kanji. / Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression. In: Cell death & disease. 2017 ; Vol. 8, No. 6. pp. e2857.
@article{61b8df60d13b41f18247c76a403e8b5d,
title = "Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression",
abstract = "Acute lymphoblastic leukemia (ALL) with mixed lineage leukemia (MLL) gene rearrangements (MLL+ALL) has a dismal prognosis and is characterized by high surface CD44 expression. Known that CD44 has the specific binding sites for a natural ligand hyaluronan (HA), we investigated biological effects of HA with different molecular sizes on MLL+ALL cell lines, and found that the addition of ultra-low-molecular-weight (ULMW)-HA strongly suppressed their thymidine uptakes. The MLL+ALL cell line lacking surface CD44 expression established by genome editing showed no suppression of thymidine uptake. Surface CD44-high B-precursor ALL cell lines other than MLL+, but not T-ALL cell lines, were also suppressed in their thymidine uptakes. The inhibition of thymidine uptakes was because of induction of cell death, but dead cells lacked features of apoptosis on cytospin smears and flow cytometric analysis. The cell death was neither blocked by pan-caspase inhibitor nor autophagy inhibitor, but was completely blocked by necrosis inhibitor necrostatin-1. Necrotic cell death was further supported by a marked release of a high-mobility protein group B1 and morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production suggested a role for inducing this necrotic cell death. ULMW-HA-triggered cell death was similarly demonstrated in surface CD44-high primary B-precursor leukemia cells. Assuming that ULMW-HA is abundantly secreted at the site of infection and inflammation, this study sheds light on understanding the mechanism of a transient inflammation-associated remission of leukemia. Further, the CD44-targeting may become an effective approach in future for the treatment of refractory B-precursor ALL by its capability of predominantly eradicating CD44-high leukemia-initiating cells.",
author = "Shin Kasai and Yoshiyuki Furuichi and Norie Ando and Keiko Kagami and Masako Abe and Takaya Nakane and Kumiko Goi and Takeshi Inukai and Sei Saitoh and Shinichi Ohno and Shogo Okazaki and Osamu Nagano and Hideyuki Saya and Kanji Sugita",
year = "2017",
month = "6",
day = "1",
doi = "10.1038/cddis.2017.249",
language = "English",
volume = "8",
pages = "e2857",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression

AU - Kasai, Shin

AU - Furuichi, Yoshiyuki

AU - Ando, Norie

AU - Kagami, Keiko

AU - Abe, Masako

AU - Nakane, Takaya

AU - Goi, Kumiko

AU - Inukai, Takeshi

AU - Saitoh, Sei

AU - Ohno, Shinichi

AU - Okazaki, Shogo

AU - Nagano, Osamu

AU - Saya, Hideyuki

AU - Sugita, Kanji

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Acute lymphoblastic leukemia (ALL) with mixed lineage leukemia (MLL) gene rearrangements (MLL+ALL) has a dismal prognosis and is characterized by high surface CD44 expression. Known that CD44 has the specific binding sites for a natural ligand hyaluronan (HA), we investigated biological effects of HA with different molecular sizes on MLL+ALL cell lines, and found that the addition of ultra-low-molecular-weight (ULMW)-HA strongly suppressed their thymidine uptakes. The MLL+ALL cell line lacking surface CD44 expression established by genome editing showed no suppression of thymidine uptake. Surface CD44-high B-precursor ALL cell lines other than MLL+, but not T-ALL cell lines, were also suppressed in their thymidine uptakes. The inhibition of thymidine uptakes was because of induction of cell death, but dead cells lacked features of apoptosis on cytospin smears and flow cytometric analysis. The cell death was neither blocked by pan-caspase inhibitor nor autophagy inhibitor, but was completely blocked by necrosis inhibitor necrostatin-1. Necrotic cell death was further supported by a marked release of a high-mobility protein group B1 and morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production suggested a role for inducing this necrotic cell death. ULMW-HA-triggered cell death was similarly demonstrated in surface CD44-high primary B-precursor leukemia cells. Assuming that ULMW-HA is abundantly secreted at the site of infection and inflammation, this study sheds light on understanding the mechanism of a transient inflammation-associated remission of leukemia. Further, the CD44-targeting may become an effective approach in future for the treatment of refractory B-precursor ALL by its capability of predominantly eradicating CD44-high leukemia-initiating cells.

AB - Acute lymphoblastic leukemia (ALL) with mixed lineage leukemia (MLL) gene rearrangements (MLL+ALL) has a dismal prognosis and is characterized by high surface CD44 expression. Known that CD44 has the specific binding sites for a natural ligand hyaluronan (HA), we investigated biological effects of HA with different molecular sizes on MLL+ALL cell lines, and found that the addition of ultra-low-molecular-weight (ULMW)-HA strongly suppressed their thymidine uptakes. The MLL+ALL cell line lacking surface CD44 expression established by genome editing showed no suppression of thymidine uptake. Surface CD44-high B-precursor ALL cell lines other than MLL+, but not T-ALL cell lines, were also suppressed in their thymidine uptakes. The inhibition of thymidine uptakes was because of induction of cell death, but dead cells lacked features of apoptosis on cytospin smears and flow cytometric analysis. The cell death was neither blocked by pan-caspase inhibitor nor autophagy inhibitor, but was completely blocked by necrosis inhibitor necrostatin-1. Necrotic cell death was further supported by a marked release of a high-mobility protein group B1 and morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production suggested a role for inducing this necrotic cell death. ULMW-HA-triggered cell death was similarly demonstrated in surface CD44-high primary B-precursor leukemia cells. Assuming that ULMW-HA is abundantly secreted at the site of infection and inflammation, this study sheds light on understanding the mechanism of a transient inflammation-associated remission of leukemia. Further, the CD44-targeting may become an effective approach in future for the treatment of refractory B-precursor ALL by its capability of predominantly eradicating CD44-high leukemia-initiating cells.

UR - http://www.scopus.com/inward/record.url?scp=85029385944&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029385944&partnerID=8YFLogxK

U2 - 10.1038/cddis.2017.249

DO - 10.1038/cddis.2017.249

M3 - Article

C2 - 28569787

AN - SCOPUS:85029385944

VL - 8

SP - e2857

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 6

ER -