Cell Division Patterns in Acute Myeloid Leukemia Stem-like Cells Determine Clinical Course: A Model to Predict Patient Survival

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease in which a variety of distinct genetic alterations might occur. Recent attempts to identify the leukemia stem-like cells (LSC) have also indicated heterogeneity of these cells. On the basis of mathematical modeling and computer simulations, we have provided evidence that proliferation and self-renewal rates of the LSC population have greater impact on the course of disease than proliferation and self-renewal rates of leukemia blast populations, that is, leukemia progenitor cells. The modeling approach has enabled us to estimate the LSC properties of 31 individuals with relapsed AML and to link them to patient survival. On the basis of the estimated LSC properties, the patients can be divided into two prognostic groups that differ significantly with respect to overall survival after first relapse. The results suggest that high LSC self-renewal and proliferation rates are indicators of poor prognosis. Nevertheless, high LSC self-renewal rate may partially compensate for slow LSC proliferation and vice versa. Thus, model-based interpretation of clinical data allows estimation of prognostic factors that cannot be measured directly. This may have clinical implications for designing treatment strategies. Cancer Res; 75(6); 940-9. Ó2015 AACR.

Frequency and Dynamics of Leukemia-Initiating Cells during Short-term Ex Vivo Culture Informs Outcomes in Acute Myeloid Leukemia Patients

“…In addition, an acute myeloid leukemia (AML) mathematical modeling of LIC proliferation was also separately shown to correlate with the clinical outcome of the patients (5). Thus, LIC quantification and their monitoring could have strong clinical applications, especially for intermediate-risk normal karyotype AMLs that account for approximately 60% of all AML patients.…”

Blood Cell Dynamics: Half of a Century of Modelling

“…Most of the published works of the beginning of this decade are in the continuity of the end of the 2000's: cyclical neutropenia treatment by G-CSF [181], [182], [71], [94], [301], CML study [139], [158], [224], [106], [48], [178], [257], AML study [275], [274], [47], granulopoiesis [262], [263], HSC study [234], [207], [277], [33], [276], [281], [218], [5], [18], [136], [74] (with two nice reviews dealing with treatments of hematological diseases [96]), [294], very few on erythropoiesis [90], [261], [68] megakaryopoiesis [269], cell fate analysis [219]. There were mathematical development of structured populations [70], [111], [67], [114] with delay equations [20], [88], [21], [15], [59], [4], …”

Less Utilized Prognostic Markers in Acute Myeloid Leukemia

“…LPC was assumed to proliferate faster than LSC while LSC had higher selfrenewal rates. The system was applied to the clinical data of 41 patients with relapsed AML [60] . As expected, considerable interindividual heterogeneity of LSC properties was observed among patients.…”

“…More importantly, high self-renewal rate was required for leukemia relapse whereas fast proliferation rate was not always required. Nevertheless, LPCs play a major role as they speed up production of leukemic blasts [60] . Other mathematical models has been established to characterize stem cells based on signaling interaction with the environment [61] and determine how stem cells coordinate homeostasis through cross-talk between genetic and epigenetic regulation [62] .…”

“…Complete remission is achievable in 65% de novo AML and 41% secondary AML. Median overall survival for these patients was 1119 days for age 16-55 years (N=554), 350 days for age [56][57][58][59][60][61][62][63][64][65] years (N = 437) and 80 days for patients aged 76-89 year old (N = 968) [1] . The French-American-British (FAB) classification of acute myeloid leukemias, the first classification established more than 40 years ago, identifies eight subtypes (M0-M7) based on morphology and cytochemistry staining.…”