The authors used MA9 cells — CD34+ human cord blood (CB) cells transduced with an MLL–AF9 construct — and showed that they are immortal and can be cultured to assume either myeloid or lymphoid phenotypes, highlighting the contribution of culture conditions in lineage determination. When injected into non-obese diabetic, severe combined immunodeficient (NS) mice, MA9 cells led to the development of both AML and ALL. However, the introduction of MA9 cells into transgenic NS mice that express the human cytokines stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin 3 not only biased the disease towards a myeloid phenotype, but resulted in a more aggressive disease, further reinforcing the role of the cytokine milieu in specifying lineage.
To further understand the nature of the LSC in MLL–AF9 leukaemias, myeloid and lymphoid lines derived from a single CB transduction were injected into β2-globulin-deficient NS mice, triggering the development of AML and ALL respectively. Intriguingly, clonal identity was confirmed between at least one case of AML and ALL, implying that an LSC can be multipotent and can promote expansion of both myeloid and lymphoid lineages, and the subsequent development of two phenotypically diverse diseases. However, further experiments established that lineage-restricted LSCs can also be targets for MLL–AF9, thus demonstrating heterogeneity within LSCs in mixed-lineage leukaemia.
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