The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment

Abstract

• Full oncogenic activity of MLL-Af4 is facilitated by lymphoid commitment and is compromised in the myeloid cell context. • The CHD domain of Af4 is sufficient to confer the linkage between lymphoid lineage and leukemic transformation.Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development. Cells expressing MLL-AF9 efficiently developed AML in NSGS mice. In contrast, MLL-Af4 cells, which were fully oncogenic under lymphoid conditions present in NSG mice, displayed compromised transformation capacity in a myeloid microenvironment. MLL-Af4 activated a self-renewal program in a lineage-dependent manner, showing the leukemogenic activity of MLL-Af4 was interlinked with lymphoid lineage commitment. The C-terminal homology domain (CHD) of Af4 was sufficient to confer this linkage. Although the MLL-CHD fusion protein failed to immortalize HSPCs in myeloid conditions in vitro, it could successfully induce ALL in NSG mice. Our data suggest that defective self-renewal ability and leukemogenesis of MLL-Af4 myeloid cells could contribute to the strong B-cell ALL association of MLL-AF4 leukemia observed in the clinic. (Blood. 2017;130(7):903-907)

Molecular processes involved in B cell acute lymphoblastic leukaemia

“…These seemingly contrasting results suggest that either the cell context can impact on the transformation process mediated by MLL-AF4 or maintaining the right level of MLL-AF4 expression is crucial, with knockdown and overexpression both having a negative impact on cell proliferation. The former interpretation is supported by recent work from the Mulloy group who revealed an impaired ability of MLL-Af4 to transform myeloid cells [ 77 ]. This lymphoid preference is driven by the Af4 partner and requires a lymphoid cellular context.…”

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

“…However, while MLL-ENL fusions occur more often, the predominant fusion found in patients with t-AML is MLL-AF9 (Meyer et al, 2018), suggesting that the selective advantage conferred by certain fusions during oncogenesis, rather than their formation frequencies, govern their prevalence in patients with leukemias. In accordance, the various MLL fusions have different transforming capacities in vivo and these are closely linked to microenvironment (Drynan et al, 2005;Krivtsov and Armstrong, 2007;Lin et al, 2017).…”

The challenges of checkpoint inhibition in the treatment of multiple myeloma

“…It is very likely that chemotherapy and antibiotic use in myeloma patients could affect composition of the gut microbiome and diminish the efficacy of checkpoint inhibitors. These data need to be weighed against the recent data that showed a survival benefit with prophylactic antibiotic use in myeloma patients undergoing induction chemotherapy 140 .…”

“…It is possible that, similar to solid tumors, oral supplementation of A. muciniphila could restore or enhance the efficacy of checkpoint inhibitors in multiple myeloma; prior exposures to antibiotics could therefore be potentially deleterious to myeloma patients being considered for immunotherapy. However, this must be weighed against the potential benefit of prophylactic antibiotics which was recently demonstrated in a large phase III trial of newly diagnosed MM patients 140 …”