Disease relevance of MEIS1

• Taken together, these data suggest that in myeloid leukemia cells MEIS1 forms trimeric complexes with PBX and HOXA9, which in turn can bind to consensus PBX-HOXA9 DNA targets [1].
• Analysis of somatic cell hybrids segregating human chromosomes allowed localization of MEIS1 to human chromosome 2p23-p12, in a region known to contain translocations found in human leukemias [2].
• The overexpression of HOXA genes was associated with overexpression of its cofactor MEIS1 in CALM-AF10+ T-ALL, reaching levels of expression similar to those observed in MLL-t AL [3].
• While HOXA9 is expressed in most cases of chronic myelogenous leukemia, MEIS1 is weakly expressed or not at all [4].
• The MEIS1 oncogene is highly expressed in neuroblastoma and amplified in cell line IMR32 [5].

Psychiatry related information on MEIS1

• Although further psychometric analysis of the MEIS is warranted, the authors found that overall emotional intelligence, emotional perception, and emotional regulation uniquely explained individual cognitive-based performance over and beyond the level attributable to general intelligence [6].

High impact information on MEIS1

• These and other studies showing that Meis1 is expressed at high levels in hematopoietic stem cells (HSCs) suggest that Meis1 may also be required for the proliferation/self-renewal of the HSC [7].
• 5. In addition, Meis1-deficient embryos lack well-formed capillaries, although larger blood vessels are normal [7].
• Likewise, in murine myeloid leukemia, transcriptional coactivation of Meis1 with HoxA7/A9 suggests that Meis1-HoxA7/9 heterodimers may evoke aberrant gene transcription [8].
• Interestingly, while the Hoxa9 N-terminal domain (NTD) is essential for cooperative transformation with wild-type Meis1, it was dispensable in Vp16-Meis1 progenitors [9].
• Surprisingly, Vp16-Meis1 (but not engrailed-Meis1) functioned as an autonomous oncoprotein that mimicked combined activities of Meis1 plus Hoxa9, immortalizing early progenitors, inducing low-level expression of Meis1-related signature genes, and causing leukemia without coexpression of exogenous or endogenous Hox genes [9].

Biological context of MEIS1

• Thus, these studies demonstrate that the homeodomain proteins, MEIS1, PBX1B, and PBX2, play an important role in megakaryocytic gene expression [10].
• This activation was not observed when MEIS1 binding sites in the TME were disrupted [10].
• The promoter activities of deletion constructs were evaluated, and a novel regulatory element termed TME (tandem repeat of MEIS1 binding element) (-219 to -182) was defined [10].
• C-terminal deletion of MEIS1 impaired transactivation without disrupting DNA binding or complex formation with HOX and PBX [11].
• HOXA10, Pbx2, and Meis1 were expressed in the stroma throughout the menstrual cycle [12].

Anatomical context of MEIS1

• HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells [1].
• Most distinct was the correlation between MLL status and MEIS1 expression in ALL-derived cell lines: 8/8 MLLmu but 0/10 MLLwt cell lines expressed MEIS1 [13].
• Here we demonstrate the expression of Pbx and Meis family cofactors in the human endometrium and their interaction with HOXA10 [12].
• Immunohistochemical staining of selected AML samples showed moderate to high levels of HOXA9 protein, primarily cytoplasmic, in leukemic myeloblasts, with weaker and primarily nuclear staining for MEIS1 [4].
• We also showed that MEIS1 can efficiently induce their conversion to leukemic stem cells, thus providing a novel model for the study of leukemic progression [14].

Associations of MEIS1 with chemical compounds

• Subsequent to TSA treatment, MEIS1 recruitment lagged behind that of HOX and PBX partners [11].
• We have previously demonstrated that homeodomain proteins, MEIS1 and PBXs, transactivate the PF4 gene through the novel regulatory element termed TME [15].
• RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb [16].
• This is the first example of a transcription factor oncoprotein (Meis1) that establishes expression of a tyrosine kinase oncoprotein (FLT3), and explains their coexpression in human leukemia [17].
• At this concentration of dimethylsulfoxide, soluble F1 also catalyzes the spontaneous synthesis of a tightly bound ATP to a level of approximately 0.15 mol per mol F1 [Gómez-Puyou, A., Tuena de Gómez-Puyou, M. & de Meis, L. (1986) Eur. J. Biochem. 159, 133-140] [18].

Physical interactions of MEIS1

• Previous studies have demonstrated that HOX-9 and HOX-10 paralog proteins are unique among HOX homeodomain proteins in their capacity to form in vitro cooperative DNA binding complexes with either the PBX or MEIS protein [1].
• (iii) Although MEIS does not cooperatively bind DNA with ANTP class HOX proteins, it does form a trimer as a non-DNA-binding partner with DNA-bound PBX-HOXD4 [19].
• Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic homeodomain protein PDX1 and switch the nature of its transcriptional activity [20].
• Functional studies showed that PBX3C and PBX3D proteins were unable to interact with the PBX-interacting factor PREP1 and weakly interacted with MEIS proteins [21].
• Here we show that PBX and Meis homeoproteins cooperatively bind the PBX-responsive sequence in vitro with the oncoprotein encoded by the non-clustered homeobox gene HOX11 activated by the t(10;14)(q24;q11) chromosomal translocation in T-cell acute lymphoblastic leukemia (T-ALL) [22].

Regulatory relationships of MEIS1

• MEIS1 enhances in vitro HOXA9-PBX protein complex formation in the absence of DNA and forms a trimeric electrophoretic mobility shift assay (EMSA) complex with these proteins on an oligonucleotide containing a PBX-HOXA9 site [1].
• A total of 89.5% of patients expressing MEIS1 co-expressed HOXA7 [23].
• These observations suggest that association with PBX and MEIS partners controls the nature of the transcriptional activity of the organ-specific PDX1 transcription factor in exocrine versus endocrine cells [20].
• These results indicate that PBX-MEIS1 complexes interact with nuclear T3 receptors to enhance T3 regulation of malic enzyme transcription in hepatocytes [24].

Other interactions of MEIS1

• We now show that in vitro DNA site selection for MEIS1 in the presence of HOXA9 and PBX yields a consensus PBX-HOXA9 site [1].
• In unadjusted models, poorer response to chemotherapy was associated with expression of HOXA7 regardless of MEIS1 status and older patients were more likely to express either gene [23].
• Furthermore, in vitro differentiation of the uninduced blastema leads to rapid down-regulation of PEG3, DLK1, and MEIS1 [25].
• We now demonstrate high-level expression of the MEIS1 and MEIS2 genes, as well as efficient expression of most other TALE family member genes in a panel of neuroblastoma cell lines [26].
• However, not all formed strong leukemogenic NUP98 fusion genes; but together with overexpression of MEIS1, all induced myeloid leukemia [14].

Analytical, diagnostic and therapeutic context of MEIS1

• By performing Western blottings and supershift assays, the binding proteins were identified as homeodomain proteins, MEIS1, PBX1B, and PBX2 [10].
• We surveyed expression of HOXA9 and MEIS1 in 24 leukemic cell lines and 80 patient samples, using RNase protection analyses and immunohistochemistry [4].
• Utilising quantitative real-time RT-PCR assays, the expression of 20 HOX genes and two known HOX co-factors, PBX1B and MEIS1, were analysed in human melanoma and breast cancer cell lines, comparing results against non-malignant cells [27].
• Chromatin immunoprecipitation confirmed co-occupancy of Hoxa9 and Meis1 on the Flt3 promoter [9].
• Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation [28].

References