Gasparetto Maura, Smith Clayton A
Division of Hematology, University of Colorado, Aurora, CO, USA.
Division of Hematology, University of Colorado, Aurora, CO, USA.
Chem Biol Interact. 2017 Oct 1;276:46-51. doi: 10.1016/j.cbi.2017.06.020. Epub 2017 Jun 20.
Multiple studies have demonstrated that ALDH1A1 is elevated in hematopoietic stem cells (HSCs). As a means to better characterize such cells, we previously developed the fluorescent ALDH1A1 substrate Aldefluor to facilitate HSC identification and isolation. This has proven useful for counting and isolating HSCs from human bone marrow, peripheral blood and cord blood as well as stem cells in other tissues and organisms. Given the high level expression of ALDH1A1, we explored its biology and that of other ALDHs in HSCs and found that ALDH1A1 and ALDH3A1 were important in metabolizing reactive aldehydes (RAlds) and reactive oxygen species (ROS). In murine models, loss of these two isoforms resulted in a variety of effects on HSC biology, increased DNA damage and predisposition to leukemia formation when combined with a genetic driver of HSC proliferation and self-renewal. Loss of ALDH activity may also predispose to marrow failure and AML in Fanconi's anemia (FA). ALDHs also have importance in mediating drug resistance in AML, may be useful in the identification of leukemia stem cells (LSCs) and ALDH activity levels may have prognostic significance. Together these findings suggest that further studying ALDH biology in AML and other blood cancers may provide important insights into malignant transformation and may point the way to the development of novel diagnostics and therapies.
多项研究表明，醛脱氢酶1A1（ALDH1A1）在造血干细胞（HSC）中表达升高。为了更好地表征此类细胞，我们之前开发了荧光ALDH1A1底物AldeFluor，以促进HSC的识别和分离。这已被证明可用于从人骨髓、外周血和脐带血以及其他组织和生物体中的干细胞中计数和分离HSC。鉴于ALDH1A1的高水平表达，我们探索了其在HSC中的生物学特性以及其他醛脱氢酶的生物学特性，发现ALDH1A1和醛脱氢酶3A1（ALDH3A1）在代谢活性醛（RALD）和活性氧（ROS）方面很重要。在小鼠模型中，这两种异构体的缺失对HSC生物学产生了多种影响，与HSC增殖和自我更新的遗传驱动因素结合时，DNA损伤增加且易患白血病。醛脱氢酶活性的丧失也可能使范科尼贫血（FA）患者易患骨髓衰竭和急性髓系白血病（AML）。醛脱氢酶在介导AML的耐药性方面也很重要，可能有助于识别白血病干细胞（LSC），并且醛脱氢酶活性水平可能具有预后意义。这些发现共同表明，进一步研究AML和其他血液癌症中的醛脱氢酶生物学特性可能为恶性转化提供重要见解，并可能为新型诊断和治疗方法的开发指明方向。
