Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space

O Akinduro,M L R Haltalli,N M Rashidi,N Ruivo,E D Hawkins,T S Weber,K R Duffy,C Lo Celso,H Ang,D Duarte

doi:10.1038/s41467-017-02376-5

O Akinduro, M L R Haltalli + Show 8 more

Open Access

https://doi.org/10.1038/s41467-017-02376-5

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Abstract

Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination.

Highlights

Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood
We used the MLL-AF9 mouse model of acute myeloid leukaemia (AML) to better understand the contribution of each of these processes. (I) We determined absolute cell numbers of AML and haematopoietic stem and progenitor cells (HSPCs). (II) We quantified the numbers of AML cells and HSPCs entering S phase per hour. (III) We measured the proportion of apoptotic cells, and the appearance of healthy and malignant cells in blood and spleen
At day 24, this resulted in 4.87 × 107 (±4.6 × 106 s.e.m) AML cells in BM contained within two tibias, two femurs and two ileac bones of each mouse analysed

Summary

Introduction

Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. The population-level paradigm for this system is the haematopoietic tree, a hierarchical commitment structure describing progressive amplification and differentiation with rare haematopoietic stem cells (HSCs) at its top[1] These self-renewing, multipotent cells give rise to a cascade of increasingly lineage-restricted progenitors that are not selfrenewing. Dual pulse-chase nucleoside analogue labelling, pioneered by Wimber and Quastler[25], identifies all cells that have entered into S phase in a given timeframe We applied it to understand the cellular dynamics underlying AML growth and parallel loss of healthy haematopoiesis. We measured absolute cell numbers, and proportions of apoptotic cells

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