MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

Abstract

Summary The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show using rigorous, independent animal models that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML.

A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence

“…Remarkably, in both cell lines we did not detect any significant defect in cell growth, despite effective knockout of ZFP64 (Figure 6E and S5C–D). We performed ChIP-seq and RNA-seq in the human retroviral MLL-AF9/Nras G12D AML cells and confirmed the exceptional level of ZFP64 occupancy at the endogenous MLL promoter and verified the ZFP64 requirement to express endogenous MLL WT , which is dispensable in MLL fusion leukemia models (Chen et al, 2017) (Figure 6F and S5E). To further corroborate this finding, we evaluated the effect of Zfp64 knockout in a mouse leukemia model in which MLL-AF9/Nras G12D oncogenes are expressed via a retroviral LTR promoter (RN2 cells) and in a knock-in leukemia model in which MLL-AF9 is expressed from the endogenous Mll promoter (Corral et al, 1996).…”

“…Both MLL fusion and MLL WT proteins are expressed in MLL -rearranged leukemia, since the MLL rearrangements is heterozygous. However, discrepancies exist in the literature regarding the essentiality of MLL WT for leukemogenesis, which may reflect different genetic targeting strategies used in these studies (Cao et al, 2014; Chen et al., 2017; Mishra et al, 2014; Thiel et al, 2010). However, recent studies have shown that MLL WT is essential to support a leukemogenic transcriptional program in the NPM1 -mutant and NUP98 -rearranged subtypes of leukemia (Kuhn et al, 2016; Xu et al., 2016).…”

Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia

“…For instance, in MLL-AF9-driven acute myeloid leukemia, germline MLL promotes proliferation and survival (Thiel et al 2010) and cooperates with MLL-AF9 for efficient transactivation of the HOXA9 locus (Milne et al 2010). Other studies suggest that germline MLL2 rather than MLL is essential for MLL-AF9 leukemogenesis; however, MLL contributes to leukemia cell survival through collaboration with MLL2 BCL2L11 BCL2L11 BCL2L11 BCL2L11 BCL2L11 BCL2L11 BCL2L11 CDKN1A CDKN1B CDKN2A CDKN2A CDKN2A CDKN2D TP53BP1 TP53BP1 TP53 TP53 -3 ( Chen et al 2017). Germline MLL is more active than MLL-AF4 in protecting CpGs from methylation, while MLL-AF4 is a more potent transcriptional activator (Erfurth et al 2008).…”

Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

“…DPY30 may, however, support MLL-rearranged leukemias by regulating the activity of endogenous MLL1 and/or MLL2, which have been shown to be important in sustaining these leukemias (57,58). Moreover, we have previously shown that DPY30 regulates the activity of the MYC oncogene through two different levels: (i) DPY30 directly promotes the expression of MYC gene, as shown in MLL-rearranged leukemia cells (17), Burkitt's lymphoma, and Jurkat cells (20), and (ii) DPY30 regulates chromatin accessibility and enables efficient binding of MYC oncoprotein to many of its genomic targeting (20).…”