Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient
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ORIGINAL ARTICLE
Functional analysis of a novel fusion protein PAX5‑KIDINS220 identified in a pediatric Ph‑like ALL patient Takuyo Kanayama1 · Toshihiko Imamura1 · Azusa Mayumi1 · Emi Soma2 · Kenichi Sakamoto1,3 · Fumihiko Hayakawa4 · Akihiko Tanizawa5 · Nobutaka Kiyokawa6 · Hajime Hosoi1 Received: 19 May 2020 / Revised: 29 June 2020 / Accepted: 7 July 2020 © Japanese Society of Hematology 2020
Abstract PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, we report the functional analysis of PAX5-K220 in vitro. We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. Luciferase reporter assay reveals that PAX5-K220 inhibits wild-type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity. Precise functional analysis of each differently partnered PAX5 fusion protein is warranted in the future for better understanding of PAX5-related translocations and their effects. Keywords PAX5 · KIDINS220 · Philadelphia chromosome-like acute lymphoblastic leukemia · B-cell differentiation arrest
Introduction
* Toshihiko Imamura [email protected]‑m.ac.jp 1
Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii‑cho, Kawaramachi‑Hirokoji, Kamigyo‑ku, Kyoto 602‑8566, Japan
2
Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
3
Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
4
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
5
Department of Human Resource Development for Cancer, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
6
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
PAX5-related fusion proteins are some of the most common fusion proteins found in B-cell precursor acute lymphoblastic leukemia (B-ALL), occurring at a frequency of 2–3% [1, 2]. The common leukemogenic mechanism of PAX5-related fusion proteins is thought to be repression of transcriptional activity of normal PAX5 via a dominant-negative effect, resulting in the arrest of B-lymphocyte differentiation at an uncommitted progenitor stage [3–6]. Because th
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