New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes

Kohlmann, Alexander; Schoch, Claudia; Dugas, Martin; Schnittger, Susanne; Hiddemann, Wolfgang; Kern, Wolfgang; Haferlach, Torsten

doi:10.1038/sj.leu.2403746

Cited by 81 publications

(82 citation statements)

References 62 publications

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“…Leukemic cells that express MLL gene fusions harbor a gene expression profile that distinguishes them from acute lymphoblastic or myeloblastic leukemia without MLL gene rearrangements. The genes most differentially expressed are HOXA5, HOXA7 and HOXA9, pivotal HOX genes in MLL-driven transformation (Hess, 2004;Kohlmann et al, 2005). MLL was reported to regulate directly HOX gene expression (Yu et al, 1995;Milne et al, 2002Milne et al, , 2005Hsieh et al, 2003;Ernst et al, 2004;Dou et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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Section: Introductionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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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: 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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“…41,42 Thus far, these four entities are combined into the first hierarchical step in the WHO classification as so-called 'AML with recurrent balanced translocations'. 8 This hierarchy of the WHO classification of AML might be amended by further addition of other reciprocal translocations, such as the rare t(8;16)(p11;p13), if unique clinical, morphologic and genetic features were established.…”

Section: Gene Expression Profiling In Aml With T(8;16) T Haferlach Et Almentioning

confidence: 99%

AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features

et al. 2009

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Balanced chromosomal rearrangements define distinct entities in acute myeloid leukemia (AML). Here, we present 13 AML cases with t(8;16)(p11;p13) with observed low incidence (13/6124 patients), but more frequent presentation in therapyrelated AML than in de novo AML (7/438 versus 6/5686, P ¼ 0.00001). Prognosis was poor with median overall survival of 4.7 months. Cytomorphology was characterized by parallel positive myeloperoxidase and non-specific esterase staining, therefore, French-American-British (FAB)-classification was impossible and origin of the AML with t(8;16) from an early stem cell with myeloid and monoblastic potential is hypothesized. Erythrophagocytosis was observed in 7/13 cases. Using gene expression profiling on 407 cases, patients with t(8;16) were compared to AML FAB subtypes with normal karyotype. Principal component analyses demonstrated that AML with t(8;16) were distinct from FAB subtypes M1, M4, M5a/b. When further compared to AML showing balanced rearrangements, that is, current WHO categories t(15;17), t(8;21), inv(16) and t(11q23)/MLL, AML with t(8;16) cases were clustered close to t(11q23)/MLL sharing commonly expressed genes. Subsequently, a pairwise comparison discriminated AML with t(8;16) from AML with t(11q23)/MLL, thus defining a highly unique signature for AML with t(8;16). In conclusion, AML with t(8;16) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features and is a specific subtype of AML.

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New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes

Cited by 81 publications

References 62 publications

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

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

AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features

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