Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia

Lin, Shuo; Luo, Roger T.; Ptasińska, Anetta; Kerry, Jon; Assi, Salam A.; Wunderlich, Mark; Imamura, Toshihiko; Kaberlein, Joseph J.; Rayes, Ahmad; Althoff, Mark J.; Anastasi, John; O’Brien, Maureen M.; Meetei, Amom Ruhikanta; Milne, Thomas A.; Bonifer, Constanze; Mulloy, James C.; Thirman, Michael J.

doi:10.1016/j.ccell.2016.10.008

Cited by 100 publications

(165 citation statements)

References 56 publications

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“…We found that almost all spreading and non-spreading targets are bound by MLL-AF4, but spreading targets are more likely to be downregulated by a loss of MLL-AF4 (Figures S3E and S3F). A recently generated FLAG tagged MLL-Af4 ChIP-seq experiment in CD34 + cord blood cells (Lin et al., 2016) allowed us to unambiguously identify MLL-Af4 binding sites in a primary transformed cell. FLAG-MLL-Af4 ChIP-seq identified almost 3,000 MLL-Af4 gene targets, similar to the number we obtained in SEM cells (Lin et al., 2016).…”

Section: Resultsmentioning

confidence: 99%

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

et al. 2017

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SummaryUnderstanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.

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Section: Resultsmentioning

confidence: 99%

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

et al. 2017

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“…6 Accordingly, these ALL cells displayed upregulation of lymphoid-signature genes and downregulation of myeloid-signature genes identified in MLL-fusion leukemia patients when compared with MLL-Af4 myeloid cells (supplemental Figure 1, available on the Blood Web site). 11 Thus, MLL-Af4 cells can induce B-ALL even in a BM environment favoring myeloid lineage development, emphasizing their lymphoid bias.…”

Section: 0e+00mentioning

confidence: 98%

“…6 The cells expressing MLL-Af4 exhibited strong predilection for lymphoid lineage and a resistance to myeloid redirection. They retained the capacity to initiate B-ALL in immunodeficient nonobese diabetic/ severe combined immunodeficiency/g (NSG) mice even after being cultured in myeloid-promoting conditions for weeks, in striking contrast to CD34 1 cells expressing the MLL-AF9 fusion protein, which could only give rise to AML after such conditioning.…”

Section: Introductionmentioning

confidence: 99%

“…They retained the capacity to initiate B-ALL in immunodeficient nonobese diabetic/ severe combined immunodeficiency/g (NSG) mice even after being cultured in myeloid-promoting conditions for weeks, in striking contrast to CD34 1 cells expressing the MLL-AF9 fusion protein, which could only give rise to AML after such conditioning. 6 We previously reported that microenvironmental cues from recipient mice can also direct the lineage decision of MLL-fusion leukemia. 7 To further understand the interplay between oncogene and microenvironment in lineage choice of MLL-fusion leukemia, we investigated the possibility of fully reprogramming the MLL-Af4 cells into AML in the myeloidbiasing mouse strain (NSG mice expressing human myeloid cytokines interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor [NSGS]), which has been shown to enhance AML development.…”

Section: Introductionmentioning

confidence: 99%

“…6 When transplanted into NSGS mice, MLL-AF9 cells initiated myeloid disease with 100% penetrance ( Figure 1D). The engrafted cells were CD33…”

Section: Cd33mentioning

confidence: 99%

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

Lin

Luo

Shrestha

et al. 2017

Blood

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• 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)

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Prognostic implications of cytogenetics in adults with acute lymphoblastic leukemia treated with inotuzumab ozogamicin

et al. 2019

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Karyotype is frequently used to predict response and outcome in leukemia. This post hoc exploratory analysis evaluated the relationship between baseline cytogenetics and outcome in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO), a humanized CD22 antibody conjugated to calicheamicin, in the phase 3, open‐label, randomized INO‐VATE trial. Data as of March 8, 2016, are presented in this analysis. Of the 326 patients randomized, 284 had screening karyotyping data (144 in the InO arm and 140 in the standard care [SC] arm). With InO, complete remission or complete remission with incomplete hematologic recovery (CR/CRi), minimal residual disease negativity rates, and overall survival (OS) were not significantly different between cytogenetic subgroups. CR/CRi rates favored InO over SC in the diploid with ≥20 metaphases, complex, and “other” cytogenetic subgroups. The OS hazard ratio favored InO over SC in the diploid with ≥20 metaphases, complex, and other cytogenetic subgroups. Generally, InO is effective and provides substantial clinical benefit in patients with R/R ALL who have specific baseline karyotypes.

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Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia

Cited by 100 publications

References 56 publications

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

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

Prognostic implications of cytogenetics in adults with acute lymphoblastic leukemia treated with inotuzumab ozogamicin

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