MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Vegi, Naidu M.; Klappacher, Josef; Oswald, Franz; Mulaw, Medhanie A.; Mandoli, Amit; Thiel, Verena N.; Bamezai, Shiva; Feder, Kristin; Martens, Joost H.A.; Rawat, Vijay P.S.; Mandal, Tamoghna; Quintanilla-Martı́nez, Leticia; Spiekermann, Karsten; Hiddemann, Wolfgang; Döhner, Konstanze; Döhner, Hartmut; Stunnenberg, Hendrik G.; Feuring‐Buske, Michaela; Buske, Christian

doi:10.1016/j.celrep.2016.05.094

Cited by 37 publications

(43 citation statements)

References 45 publications

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“…Preliminary analysis of gene expression data from patient samples reinforces the likely and previously unrecognised importance of this additional MEIS family member in human AML. These novel findings complement work identifying MEIS2 as differentially expressed and functionally critical in RUNX1-RUNX1T1-mediated AML, 11 possibly extending the relevance of Meis2 to a range of leukemic subgroups.…”

Section: Introductionsupporting

confidence: 69%

“… 38 However, upregulation of HOXA9 also correlates to high MN1 expression in AML patients with complex karyotype/loss of chromosome 5 or 7. 39 As upregulation of MEIS2 was recently reported in the context of patients with the RUNX1-RUNX1T1 translocation, 11 we were interested in further assessing relationships between MEIS1, MEIS2 and MN1. Analysis of an in-house data set comprised of patients with AML, MDS, therapy-related AML (tAML) or therapy-related MDS (tMDS), AML subsequent to MDS was consistent with an inverse correlation between HOXA9 and MEIS1 expression compared to expression of MN1 (Welch’s two-sample t -test, P <0.05) ( Figure 5d ).…”

Section: Resultsmentioning

confidence: 99%

“… 15 This raises the interesting possibility that Meis2 , rather than Meis1 , is most critical to MN1 leukemogenic activity, a possibility further supported by reports of upregulated Meis2 in AML and ALL cell lines, 49 a murine AML model driven by co-overexpression of Hoxa9 and Meis1 , 50 and patient samples and human cell lines characterised by the RUNX1-RUNX1T1 translocation. 11 …”

Section: Discussionmentioning

confidence: 99%

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Meis2 as a critical player in MN1-induced leukemia

Lai¹,

Norddahl²,

Maetzig³

et al. 2017

Blood Cancer J.

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Meningioma 1 (MN1) is an independent prognostic marker for normal karyotype acute myeloid leukemia (AML), with high expression linked to all-trans retinoic acid resistance and poor survival. MN1 is also a potent and sufficient oncogene in murine leukemia models, strongly dependent on the MEIS1/AbdB-like HOX protein complex to transform common myeloid progenitors, block myeloid differentiation, and promote leukemic stem cell self-renewal. To identify key genes and pathways underlying leukemic activity, we functionally assessed MN1 cell phenotypic heterogeneity, revealing leukemic and non-leukemic subsets. Using gene expression profiling of these subsets combined with previously published comparisons of full-length MN1 and mutants with varying leukemogenic activity, we identified candidate genes critical to leukemia. Functional analysis identified Hlf and Hoxa9 as critical to MN1 in vitro proliferation, self-renewal and impaired myeloid differentiation. Although critical to transformation, Meis1 knockdown had little impact on these properties in vitro. However, we identified Meis2 as critical to MN1-induced leukemia, with essential roles in proliferation, self-renewal, impairment of differentiation and disease progression in vitro and in vivo. Here, we provide evidence of phenotypic and functional hierarchy in MN1-induced leukemic cells, characterise contributions of Hlf, Hoxa9 and Meis1 to in vitro leukemic properties, and reveal Meis2 as a novel player in MN1-induced leukemogenesis.

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Section: Introductionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Meis2 as a critical player in MN1-induced leukemia

Lai¹,

Norddahl²,

Maetzig³

et al. 2017

Blood Cancer J.

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“…VENTX induced AML in all transplanted mice in collaboration with AML1-ETO, characterizing VENTX as a novel collaborative partner of AML1-ETO. With this, VENTX is among the first homeobox genes shown to cooperate with AML1-ETO, as we could just recently demonstrate that the TALE homeobox gene MEIS2 collaborates with the fusion in inducing AML [16]. It also demonstrates that the transcription factor AML1-ETO can collaborate with its own class as VENTX is a bona fide transcription factor.…”

Section: Discussionmentioning

confidence: 92%

VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice

et al. 2016

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Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML.

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“…Subsequently, cells were washed and cell counts were determined via trypan blue exclusion. Colony forming cell unit (CFC) assays were performed as described previously 14 . In all cases cell numbers placed in methylcellulose were calculated according to the initial cell number at the start of the experiment, not taking into account any cell loss during the incubation time.…”

Section: Methodsmentioning

confidence: 99%

Somatostatin receptor mediated targeting of acute myeloid leukemia by photodynamic metal complexes for light induced apoptosis

Vegi

Chakrabortty

Zegota

et al. 2020

Sci Rep

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Acute myeloid leukemia (AML) is characterized by relapse and treatment resistance in a major fraction of patients, underlining the need of innovative AML targeting therapies. Here we analysed the therapeutic potential of an innovative biohybrid consisting of the tumor-associated peptide somatostatin and the photosensitizer ruthenium in AML cell lines and primary AML patient samples. Selective toxicity was analyzed by using CD34 enriched cord blood cells as control. Treatment of OCI AML3, HL60 and THP1 resulted in a 92, and 99 and 97% decrease in clonogenic growth compared to the controls. Primary AML cells demonstrated a major response with a 74 to 99% reduction in clonogenicity in 5 of 6 patient samples. In contrast, treatment of CD34 + cB cells resulted in substantially less reduction in colony numbers. Subcellular localization assays of RU-SST in OCI-AML3 cells confirmed strong co-localization of RU-SSt in the lysosomes compared to the other cellular organelles. our data demonstrate that conjugation of a Ruthenium complex with somatostatin is efficiently eradicating LSc candidates of patients with AML. this indicates that receptor mediated lysosomal accumulation of photodynamic metal complexes is a highly attractive approach for targeting AML cells. Acute myeloid leukemia (AML) is initiated and propagated by cancer stem cells. Although these leukemic stem cells (LSCs) initially respond to chemotherapy, most patients relapse and die from the disease 1. One explanation is that current therapies only eliminate the tumor bulk which lacks leukemic stem cell properties whereas the LSCs are relatively insensitive. Growing knowledge of the molecular landscape of AML has led to clinical testing of new drugs against driver mutations as well as antibody-based therapies against cell surface proteins with partly disappointing results 2-5. Thus, for the majority of patients there is therapeutic standstill and the urgent need for innovative treatment approaches. Tumor-associated peptides provide attractive characteristics for AML-targeted strategies such as easy availability, convenient purification and storage. In addition, they are less immunogenic, have a high tissue penetration and a high affinity to cellular biomarkers. They provide a rapid clearance from the body and are excellent candidates for straight forward conjugation strategies. It has been shown that somatostatin receptors (SSTR) are expressed on leukemias such as T-cell leukemia and AML 6,7. Using a somatostatin radiobinding assay it was demonstrated that around 12.5% of AML cases express somatostatin receptors 6. Previously, it has been shown that primary AML progenitor cells, characterized by the co-expression of CD34 and CD117 express the somatostatin receptor (SSTR) subtype 2 and that the expression of the SSTR2 receptor was not restricted to the immature CD34 + CD117 + compartment, but also detected on more differentiated AML blasts. Using a transwell migration assay, it was demonstrated that the migration of AML cells towards a gradient

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MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML

Cited by 37 publications

References 45 publications

Meis2 as a critical player in MN1-induced leukemia

Meis2 as a critical player in MN1-induced leukemia

VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice

Somatostatin receptor mediated targeting of acute myeloid leukemia by photodynamic metal complexes for light induced apoptosis

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