Initiation of MLL-rearranged AML is dependent on C/EBPα

Ohlsson, Ewa; Hasemann, Marie Sigurd; Willer, Anton; Lauridsen, Felicia Kathrine Bratt; Rapin, Nicolas; Jendholm, Johan; Porse, Bo T.

doi:10.1084/jem.20130932

Cited by 67 publications

(74 citation statements)

References 27 publications

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“…Here we provide novel insights on this process and show that the presence of C/EBPα p42 is required not only to initiate TRIB2 AML, but also for TRIB2 to cooperate with C/EBPα (p42 loss and increased p30) in driving AML disease. Our data support the emerging notion that C/EBPα functions in the initial transformation, as supported by the data showing that C/EBPα regulated a transcriptional program essential for initiation yet dispensable for the maintenance of MLL-ENL disease (18). Our data clearly show loss of C/EBPα p42 via TRIB2 induced ubiquitin-mediated degradation and excess p30 expression cooperates to accelerate AML.…”

Section: Discussionsupporting

confidence: 88%

“…Although conditional Cebpa knockout mice do not develop disease, the loss of Cebpa in adult HSCs leads to an increased number of functional and proliferative HSCs (15,17) and loss of HSC pool maintenance in serial transplantations (16). Cebpa expression is required for AML disease initiation by the oncogene MLL-ENL but not for disease maintenance (18). In contrast, Cebpa is required for the maintenance of Hoxa9/Meis1 AML disease (19).…”

Section: Introductionmentioning

confidence: 99%

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The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive.Using mouse genetics our data reveal that in the complete absence of C/EBPα TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30 were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate the molecular mechanism involved in degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C-terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2 positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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“…It has been reported that partial myelomonocytic differentiation is required for MLL-AF9-induced AML, 17 likely due to myeloid transcription factor contribution to the oncogenic program. 18,19 Thus, there is the possibility that an essential cooperation exists between lymphoid-specific factors and MLL-Af4, which provides the lymphoid preference of MLL-Af4 cells. It was reported that 2 t(4;11) ALL patients displayed a myeloid shift after CD19-directed therapy.…”

Section: 0e+00mentioning

confidence: 99%

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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“…Chromosomal translocations of band q23 of chromosome 11 of the mixed lineage leukemia (MLL) gene are common in AML and are associated with poor prognosis. 59,60 No effective treatment is currently available for patients affected by the disease. The discovery of new therapeutic agents against the disease is vital.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Initiation of MLL-rearranged AML is dependent on C/EBPα

Abstract: C/EBPα collaborates with MLL-ENL to activate a group of genes that, together with Hoxa9 and Meis1, are responsible for the early events that transforms normal hematopoietic cells into leukemic cells

Cited by 67 publications

References 27 publications

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

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

Targeting CDK6 in cancer: State of the art and new insights

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