Digitalization of a non-irradiated acute myeloid leukemia model

Abstract

BackgroundComputer-aided, interdisciplinary researches for biomedicine have valuable prospects, as digitalization of experimental subjects provide opportunities for saving the economic costs of researches, as well as promoting the acquisition of knowledge. Acute myeloid leukemia (AML) is intensively studied over long periods of time. Till nowaday, most of the studies primarily focus on the leukemic cells rather than how normal hematopoietic cells are affected by the leukemic environment. Accordingly, the conventional animal models for AML are mostly myeloablated as leukemia can be induced with short latency and complete penetrance. Meanwhile, most previous computational models focus on modeling the leukemic cells but not the multi-tissue leukemic body resided by both leukemic and normal blood cells. Recently, a non-irradiated AML mouse model has been established; therefore, normal hematopoietic cells can be investigated during leukemia development. Experiments based on the non-irradiated animal model have monitored the kinetics of leukemic and (intact) hematopoietic cells in multiple tissues simultaneously; and thus a systematic computational model for the multi-tissue hematopoiesis under leukemia has become possible.ResultsIn the present work, we adopted the modeling methods in previous works, but aimed to model the tri-tissue (peripheral blood, spleen and bone marrow) dynamics of hematopoiesis under leukemia. The cell kinetics generated from the non-irradiated experimental model were used as the reference data for modeling. All mathematical formulas were systematically enumerated, and model parameters were estimated via numerical optimization. Multiple validations by additional experimental data were then conducted for the established computational model. In the results, we illustrated that the important fact of functional depression of hematopoietic stem/progenitor cells (HSC/HPC) in leukemic bone marrow (BM), which must require additional experiments to be established, could also be inferred from our computation model that utilized only the cell kinetics data as the input.ConclusionThe digitalized AML model established in the present work is effective for reconstructing the hematopoiesis under leukemia as well as simulating the hematopoietic response to leukemic cell expansion. Given the validity and efficiency, the model can be of potential utilities in future biomedical studies; additionally, the modeling method itself can be also applied elsewhere.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0308-x) contains supplementary material, which is available to authorized users.

System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia

“…On the contrary, given the typical pre-conditioned leukemia models utilized in most of previous studies, the physiology of native leukemogenesis is destroyed, i.e. non-leukemic cells in the leukemic host are no longer the “normal” cells because they are heavily damaged by the myeloablative manipulations and thus deviant far from the normal cellularity [ 7 , 9 , 27 – 30 ]. Gene expressions in those study designs (other than ours) cannot represent in vivo functions; hence if in those cases, Maff / Egr3 regulations on HSC cell cycle could not have been inferred.…”

“…In our previous research, we found that in leukemic BM, the HPC count increased and the rate that HSCs differentiate into HPCs was high at the beginning; meanwhile, the differentiation of HSCs towards HPCs was almost shut off later and the HPC count decreased acutely after day 14 [ 9 ]. Furthermore, significantly increased quiescence of HSCs was observed at the late stage of leukemia [ 7 ].…”

“…These cellular-level results render a hint that HSCs respond to leukemia with a process of cancerization/self-protection. When leukemia emerges, HSCs accelerate their cell cycles to proliferate into more functional blood cells to compensate cell loss; on the other hand, as leukemic cells become dominant and outgrow normal cells, most HSCs stay in the quiescent state, which is far less sensitive to environmental affects [ 7 , 9 , 31 , 32 ]. Here in this study, by revealing how Maff and Egr3 act on cell cycle, we find the trait of “cancerization/self-protection” on the molecular level.…”

“…However, we also discovered that both Maff and Egr3 were highly expressed in hematopoietic stem cells (HSCs) under leukemia (especially at the late stage, i.e. ≥ day 14), in which the cell cycles of most HSCs were heavily suppressed [ 7 – 9 ]. Therefore, the molecular mechanisms of how Maff and Egr3 act on cell cycle and why the two functionally-opposite genes are both highly expressed under leukemia, remain to be revealed.…”

Advancing Systems Biology in the International Conference on Intelligent Biology and Medicine (ICIBM) 2015

“…In the next paper, Li et al digitalized a novel animal model for acute myeloid leukemia, which accounted for both leukemic and normal blood cells in the disease [4]. Specifically, the authors modeled multi-tissue hematopoietic dynamics in the leukemic body.…”