Minami Mariko, Sakoda Teppei, Kawano Gentaro, Kochi Yu, Sasaki Kensuke, Sugio Takeshi, Jinnouchi Fumiaki, Miyawaki Kohta, Kunisaki Yuya, Kato Koji, Miyamoto Toshihiro, Akashi Koichi, Kikushige Yoshikane
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, 812-8582, Japan.
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan.
Leukemia. 2025 Apr;39(4):844-853. doi: 10.1038/s41375-025-02530-9. Epub 2025 Feb 20.
Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34CD38 fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34CD38 fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34CD38TIM-3 short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34 differentiated APL cells did not. Furthermore, CD34CD38TIM-3 short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.
急性髓系白血病（AML）的白血病干细胞（LSCs）可在CD34⁺CD38⁻亚群中富集，并在体内重建人类AML。然而，在占所有AML病例10%且由早幼粒细胞白血病-维甲酸受体α（PML::RARα）融合基因驱动的急性早幼粒细胞白血病（APL）中，由于难以在体内有效重建人类APL，LSCs的存在长期以来一直未被确定。在此，我们表明，短型异构体APL（一种由PML基因不同断点定义的APL亚型）的LSCs集中在CD34⁺CD38⁻亚群中，并表达T细胞免疫球蛋白粘蛋白-3（TIM-3）。与其他类型的APL相比，短型APL细胞表现出独特的基因表达特征，包括与LSC相关的基因。此外，CD34⁺CD38⁻TIM-3⁺短型APL细胞在异种移植模型中以高浸润效率有效重建人类APL，而CD34⁺分化的APL细胞则不能。此外，CD34⁺CD38⁻TIM-3⁺短型APL细胞在连续移植后重建白血病细胞。因此，短型APL由自我更新的APL-LSCs进行分层组织。在一部分APL中鉴定LSCs并建立有效的患者来源异种移植模型可能有助于进一步了解APL白血病发生机制，并设计针对根除APL LSCs的个体化治疗方案。
