Exploring biological overlap between in vivo and in vitro stem and progenitor compartments in healthy hematopoiesis and acute myeloid leukemia

Abstract

Together, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) oversee lifelong hematopoiesis. While HSC self-renewal and multilineage differentiation capacity are experimentally assayed through in vivo xenotransplantation assays, HPCs give rise to lineage restricted colonies readout in vitro. Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, canonically believed to be driven exclusively by leukemic stem cells (LSCs) however recent findings have revealed the progeny of LSCs, leukemic progenitor cells (LPCs), have unanticipated clinical significance and are not to be disregarded. We postulate that overlapping stem and progenitor cell functions in healthy and diseased states have been obscured because of conventional hematopoietic assay systems enforcing an artificial dichotomy between the two compartments. Accordingly, the aim of this work was to generate a novel experimental protocol for the evaluation of the in vivo engraftment capacity of LPCs and HPCs obtained from in vitro CFU assay methods. Our preliminary results indicate that HPCs and LPCs displayed in vivo healthy hematopoietic and AML disease reconstitution capacity, respectively. HPC and LPC primary xenografts persisted through secondary xenotransplantation assays, demonstrating self- renewal—a feature not classically associated with progenitors. By following the protocol and recommendations presented henceforth, HPCs and LPCs can be screened for engraftment capacity in an optimized manner, enabling efficient and more precise functional characterization of these clinically relevant cell populations. This work has the potential to improve our understanding of hierarchical arrangement in both the healthy hematopoietic system and AML and may lead to the identification of a unique subset of progenitor cells with long-term in vivo reconstitution capacity.