The molecular signature of AML with increased ALDH activity suggests a stem cell origin

Abstract

Enrichment of leukemic blasts with a stem cell phenotype correlates with poor survival in acute myeloid leukemia (AML). In this context, measurement of the stem cell marker aldehyde-dehydrogenase (ALDH) activity can distinguish poor prognosis cases with increased fractions of ALDH-positive cells (ALDH-numerous AML) and favorable outcome cases with low percentages (ALDH-rare AML). It has been shown that ALDH-numerous AML favor leukemic engraftment in xenotransplantation assays which suggests increased leukemic stem cell (LSC) potential. To test if this reflects an immature cell of origin, comparative gene-expression studies of CD34 leukemic blasts were performed. This analysis revealed increased expression of LSC and HSC signatures in ALDH-numerous AML, whereas ALDH-rare AML were enriched for a progenitor signature. The enrichment of stemness-associated transcriptional programs suggests that ALDH-numerous AML derive from immature hematopoietic progenitors and offers an explanation for the poor prognosis and therapy resistance of this subgroup which is likely caused by inherited stem cell properties.

Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics

“…Their quiescent status is a key point as well, since it protects against drugs that target actively cycling cells, making them resistant to most available tyrosine kinase inhibitors (Deshpande et al, 2006;Thielen et al, 2016). Additionally, apoptosis entrance protection (de Figueiredo-Pontes et al, 2008) and aging avoidance (Kronenwett et al, 2005) have been described among other mechanisms to explain cell persistence and relapse occurrence (Bertrand et al, 2012;Blume et al, 2018;de Figueiredo-Pontes et al, 2008;Huang et al, 2015;Lainey et al, 2012;Picot et al, 2017;Qiu et al, 2014).…”

“…These abnormalities, in addition to blast morphology and differentiation stage arrest, are used for diagnosis, subtype definition, and risk stratification (Huang et al, 2015;Wang et al, 2017;Warner et al, 2004). AML is the most well-known and well described type of leukemia, yet new therapies are needed to cure it and to improve its survival rate (Blume et al, 2018;De Grandis et al, 2017;Garg, Shanmukhaiah et al, 2016;Huang et al, 2015;Qiu et al, 2014;Quek et al, 2016;Wang et al, 2017;Yabushita et al, 2018). High-dose chemotherapy is effective in less than 50% of patients (Mohammadi et al, 2016), and this is associated with the survival of a chemotherapy-resistant pool and relapse occurrence (Blume et al, 2018;Bonardi et al, 2013;Bosman, Schuringa, Quax, & Vellenga, 2013;Garg, Shanmukhaiah et al, 2016;Goardon et al, 2011;Mohammadi et al, 2016;Pearce et al, 2005;Qiu et al, 2014;Yabushita et al, 2018;Zeijlemaker et al, 2016).…”

“…Higher values of forward scatter and side scatter (SSC) in LSCs have been observed in comparison with HSCs (Terwijn et al, ), which indicate that malignant primitive cells are larger and have more cytoplasmic complexity than their normal counterparts for unknown reasons (Terwijn et al, ). In some reports, SSC was enough to segregate these populations (Blume et al, ; Garg, Ghosh et al, ; Terwijn et al, ; van Rhenen et al, ), although LSCs were observed in the SSC‐low population (Blume et al, ; van Rhenen et al, ). Aberrant aldehyde dehydrogenase activity is also widely associated with the LSC population (Blume et al, ; Terwijn et al, ; Wang et al, ), although it is not a surface marker.…”

“…Primitively altered cells have similarities with their normal counterparts, and some properties favor their survival (Blume et al, ; Castor et al, ). As discussed earlier, endosteal niche occupation is proposed to be one resistance mechanism (Zhi et al, ) that functions through the mechanical protection of chemotherapeutic drugs (Bertrand et al, ; Valent et al, ).…”

“…It is hypothesized that when HSCs are transformed, accumulated blasts exhibit less atypical membrane proteins, resembling HSCs and having more primitive characteristics (Deshpande et al, ). When progenitors are transformed (and in this case, the granulocyte–monocyte progenitor is mainly affected), leukemic cells exhibit morphology and membrane protein expression associated with more mature cells (Blume et al, ; Goardon et al, ; van Rhenen et al, ). Importantly, regardless of morphology and membrane protein expression, the proportion of LSCs varies, which also reflects the prognosis (Garg, Ghosh et al, ; Picot et al, ).…”