Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

Abstract

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse.

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

“…Typical genetic alterations associated with AML are chromosomal translocations and abnormal fusion protein formation, such as BCL-ABL, AML1-ETO, RUNX1/RUNX1T1, PML/RARα, and DEK/ NUP214 (Leo et al, 2013;Oancea 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).…”

“…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).…”

“…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.…”

“…Numerous patients with AML achieve remission after standard chemotherapy, yet relapse is equally common (Bonardi et al, ; Qiu et al, ; Wang et al, ; Zeijlemaker et al, ). In these situations, a high proportion of patients show immunophenotypic changes to a more primitive stage (Langebrake et al, ; Wang et al, ; Zeijlemaker et al, ). The hypothesis behind this phenomenon is that the remaining cells are more quiescent and more resistant and leukemogenic.…”

“…CD123 was the first described LSC-specific antigen (de Figueiredo-Pontes et al, 2008;Yabushita et al, 2018). The panel CD34 + CD38 − CD123 + is widely used for LSC characterization (Bertrand et al, 2012;de Figueiredo-Pontes et al, 2008;De Grandis et al, 2017;Hosen et al, 2007;Nomdedeu et al, 2011;van Rhenen et al, 2007;Warner et al, 2004;Zhi et al, 2016), and its presence is associated with a poor prognosis (Garg, Shanmukhaiah et al, 2016;Nomdedeu et al, 2011;Yabushita et al, 2018), since this population appears to have chemotherapy escaping skills (Mohammadi et al, 2016;Wang et al, 2017) and is associated with unfavorable cytogenetics (Yabushita et al, 2018).…”