Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs

Abstract

Spatial localization of primitive leukemic cells is restricted to niches shared with their normal counterparts, and their ability to retain occupancy of these niches is rivaled by normal HSPCs.

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

“…Immature CD34 + leukemic cells were located in the endosteal regions of bone indicating that they shared hematopoietic niches C.F. Krombholz et al 604 haematologica | 2016; 101(5) 41 The lineage composition of engrafted JMML cell progeny clearly differed from that of xenotransplanted cord blood-derived healthy CD34 + cells, where B cells predominated and only minor myeloid populations were observed. Importantly, xenotransplanted mice showed a chronic disease course with a median survival of more than 20 weeks.…”

Tumor microenvironment: Sanctuary of the devil

“…Recent data indicated that leukemic cells hijack the homeostatic mechanisms of normal HSCs and take refuge in the BM niche [19,20] (Fig. 1).…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…Treatments targeting self-reinforcing leukemic niches especially when combined with conventional chemotherapy or molecular drugs might represent additional therapeutic options that might fulfill this clinical requirement. Various studies have demonstrated that LSCs and HSCs might share the same bone marrow niches [25,26,32] and compete for vacant niches as the number of these areas within the BM is limited [29]. Since these malignant niches provide a shelter for LSCs [79,82,83] and also specify their self-renewal properties [10,22,23] an attractive therapeutic strategy could be to dislodge these cells from their niche by targeting the CXCR4/CXCL12 interaction.…”

“…Recently, a phase I/II clinical trial based on this combination has provided beneficial results [106] and additional trials with Plerixafor with or without G-CSF in combination with conventional chemotherapy are currently ongoing as front-or second-line therapy in AML. Even more recently, an exciting observation was made: CXCR4 targeting combined with healthy cord blood HSPC (CBHPSCs) infusions appears to significantly improve allogeneic HSCT results, due to the fact that these cells might potentially function as effector cells [32]. In co-transplantation experiments, CB-HPSCs were able to out-compete leukemia initiating cells (L-ICs) for BM niche occupancy in a cell dose-dependent manner and ultimately disrupted L-IC long-term renewal.…”

“…However, in another xenotransplation mouse model, human leukemic cells with various genetic defects did not deplete normal HSCs, but rather impaired their differentiation at the level of HSCprogenitor cell transition [31]. Recently, an even more interesting observation indicated that except for pre-established leukemic disease, primary leukemia-initiating cells (L-ICs) were consistently outperformed by normal cord blood (CB) CD341 cells for BM niche occupancy in a cell dose dependent manner [32]. Notably, the results achieved by both of these studies might be explained by the recent observation that leukemic infiltration can induce progressive HSC quiescence by down-regulating cell-cycle genes and up-regulating several genes including Hes-1 and Egr3 [33].…”