A Mouse Model Reveals Lineage Plasticity in MLL–AF4 Pro-B ALL

In approximately 10% of patients with pro-B acute lymphoblastic leukemia (ALL), a t(4;11)(q21;q23) translocation fuses mixed-lineage leukemia (MLL) to AF4, generating a fusion protein that is associated with a poor prognosis. The lack of MLL–AF4 ALL mouse models has limited understanding of the disease, prompting Lin, Luo, and colleagues to develop a mouse model via retroviral transduction of MLL–AF4. Retroviral titers were too low to sufficiently transform mouse hematopoietic stem/progenitor cells (HSPC), but a hybrid construct fusing human MLL to mouse Af4 resulted in a higher retroviral titer that was sufficient to transform murine HSPCs. The human and hybrid fusion proteins regulated largely overlapping sets of genes; however, MLL–Af4- transformed murine HSPCs induced AML in vivo, whereas MLL–Af4–transformed human HSPCs induced development of pro-B ALL that had the cellular and molecular characteristics of the human disease. MLL–Af4 ALL recapitulated the pro-B developmental stage, but a different leukemic fusion, MLL–AF9, induced pre-B stage ALL by inducing expression of distinct but overlapping sets of target genes, indicating that different MLL fusion partners contribute to distinct gene expression patterns and types of leukemia. The hybrid fusion protein upregulated B lymphoid genes and downregulated myeloid genes, and myeloid cells expressing the hybrid protein maintained lymphoid lineage potential. Such lineage plasticity was also observed in cells from a pediatric patient with refractory t(4;11) pro-B ALL who was treated with the bispecific CD19 targeting antibody blinatumomab and developed t(4;11) AML upon relapse. The relapsed t(4;11) AML cells, which showed upregulation of many MLL–Af4-induced B-cell genes, resulted in the development of B-ALL when transplanted into mice. These findings suggest that MLL–Af4/AF4 cells can switch to a myeloid state due to environmental pressure, but maintain a lymphoid preference. This lineage plasticity may allow for cells to escape therapeutic targeting and develop resistance.

Lin S, Luo RT, Ptasinska A, Kerry J, Assi SA, Wunderlich M, et al. Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia. Cancer Cell 2016;30:737–49.