Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model

Abstract

Although NOD-SCID IL2Rγ (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, the expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis chronic myeloid leukemia patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in the expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL and MLL-AF9 leukemias can be studied in detail.

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

“…Overall, our work describes a versatile humanized niche model for studying both normal and leukemic human hematopoietic cell biology, particularly for the less aggressive subtypes that fail to engraft in NSG mice. Recent reports demonstrate the use of humanized bone ossicles for the study of malignant hematopoiesis (11)(12)(13)(14)(15)(16). Nevertheless, in all of these models, hMSCs were first induced to form bone ossicles before malignant hematopoietic cells were injected intrascaffold, making the duration of the whole experiment between 20 and 34 weeks compared with only 10 to 12 weeks in our study.…”

“…By merging knowledge from biomaterials, tissue engineering, and cell-implantation fields, investigators have generated new models to mimic the native human hematopoietic microenvironment within s.c. 3D structures (4)(5). Using human mesenchymal stromal cells (hMSCs) as stromal cell support within bone-forming implants, researchers have studied normal (6)(7)(8)(9)(10) and malignant (11)(12)(13)(14)(15)(16) hematopoiesis.…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…153 Likewise, several laboratories are developing 3-dimensional (3D) niche models that mimic human bone structure and composition to propagate primary specimens both in vitro and in vivo upon implantation to mice. Such models were successfully used to engraft AMLs, blast crisis CML, [154][155][156] and a limited number of MPNs (myelofibrosis). 157 These emerging models represent invaluable and cost-effective platforms for preclinical studies.…”

Leukemias and bones: humanizing the niche in mice

“…The Schuringa team has previously reported equivalent findings using the same scaffold/allogeneic human MSC implants, but making use of human cord blood CD34 1 cells genetically modified to express leukemia oncogenes (BCR-ABL and MLL-AF9). 2 Higher frequencies of leukemia development and more consistent stemness were observed in the huBM-sc than in the muBM-iv model. 4 Here as well, the malignant clonal diversity was more effectively recapitulated in the presence of MSC support.…”