PRDM14 Expression Research Articles

Prdm14 acts upstream of islet2 transcription to regulate axon growth of primary motoneurons in zebrafish

The precise formation of three-dimensional motor circuits is essential for movement control. Within these circuits, motoneurons (MNs) are specified from spinal progenitors by dorsoventral signals and distinct transcriptional programs. Different MN subpopulations have stereotypic cell body positions and show specific spatial axon trajectories. Our knowledge of MN axon outgrowth remains incomplete. Here, we report a zebrafish gene-trap mutant, short lightning (slg), in which prdm14 expression is disrupted. slg mutant embryos show shortened axons in caudal primary (CaP) MNs resulting in defective embryonic movement. Both the CaP neuronal defects and behavior abnormality of the mutants can be phenocopied by injection of a prdm14 morpholino into wild-type embryos. By removing a copy of the inserted transposon from homozygous mutants, prdm14 expression and normal embryonic movement were restored, confirming that loss of prdm14 expression accounts for the observed defects. Mechanistically, Prdm14 protein binds to the promoter region of islet2, a known transcription factor required for CaP development. Notably, disruption of islet2 function caused similar CaP axon outgrowth defects as observed in slg mutant embryos. Furthermore, overexpression of islet2 in slg mutant embryos rescued the shortened CaP axon phenotypes. Together, these data reveal that prdm14 regulates CaP axon outgrowth through activation of islet2 expression.

Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL

Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression.

Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors

Understanding the heterogeneous genetic mechanisms of tumor initiation in lymphoid leukemias (LL) will lead to improvements in prognostic classification and treatment regimens. In previous studies of mouse leukemias, we showed that retroviral insertion at the Evi32 locus leads to increased expression of Prdm14, a pluripotency gene implicated in the self-renewal capacity of embryonic stem cells and the early stages of breast cancer. Here we show that PRDM14 is also overexpressed in ~25% of human lymphoid neoplasms, with increased frequencies in T-cell acute LL (T-ALL) and hyperdiploid precursor B-cell acute LL (pre-B ALL). To test if Prdm14 overexpression could initiate leukemia, mice were transduced with bone marrow (BM) cells transfected with a Prdm14 expression vector. Lymphoid leukemias developed in 96% of female mice and 42% of male mice. Prior to the onset of leukemia, differentiation of transduced cells was biased up to 1000-fold towards cells with features of common lymphoid progenitors (CLP), and lymphoid differentiation showed a relative block at the pro-B stage. Microarray gene expression analysis of expanded CLP-like cells prior to the onset of leukemia demonstrated upregulation of genes involved in pluripotency, tumor initiation, early B-lineage commitment, Wnt/Ras signaling, and the epithelial-to-mesenchymal transition. Among the dysregulated genes were imprinted genes and non-coding RNAs including Dlk1 and Meg3, which are also key pluripotency mediators. Heightened expression of the estrogen-dependent oncogene, Myb, in tumors suggests a basis for the increased frequency of cancer in female mice. These data provide the first direct evidence for the association of Prdm14 with cancer initiation in an in vivo mouse model and in human lymphoid malignancies, while suggesting mechanisms for Prdm14’s mode of action.

Relationship between the expression of PRDM14 in non-small cell lung cancer and the clinicopathologic characteristics

背景与目的锌指蛋白转录抑制因子(positive regulatory domain zinc finger protein, PRDM)是一个有关人类肿瘤形成的转录调节因子家族，在细胞分化和恶性变中发挥重要作用。PRDM14是PRDM家族的成员之一。本研究的目的是检测PRDM14在非小细胞肺癌组织中的表达情况并探讨其与非小细胞肺癌的临床病理因素的关系。方法采用免疫组织化学方法检测70例非小细胞肺癌标本和7例癌旁组织中PRDM14的表达。采用Western blot方法检测42例非小细胞肺癌组织和癌旁肺组织中PRDM14蛋白的表达。结果7例癌旁肺组织中PRDM14弱表达，在70例非小细胞肺癌组织标本中，有8例为PRDM14阴性表达(11.43%)，9例为PRDM14弱阳性表达(12.86%)，36例PRDM14阳性表达(51.43%)，有17例PRDM14强阳性表达(24.29%)，PRDM14的表达情况与非小细胞肺癌的分化程度(P=0.046)和组织学类型(P=0.047)有关，PRDM14在高分化腺癌、鳞癌中表达最高，在中分化腺癌、鳞癌中表达次之，在低分化腺癌、鳞癌表达最低，PRDM14在腺癌中的表达高于鳞癌。Western blot结果表明PRDM14的蛋白在癌旁肺组织和肺腺癌、鳞癌组织的表达水平存在显著差异，PRDM14在非小细胞肺癌组织中的表达水平高于癌旁肺组织(P＜0.001)，而且与非小细胞肺癌的分化程度有关(P=0.017)，在高、中分化腺癌、鳞癌中的表达高于在低分化腺癌、鳞癌中的表达。结论PRDM14在癌旁肺组织中低表达，在非小细胞肺癌组织中高表达，其表达水平与非小细胞肺癌的分化、组织学类型有关，可能在非小细胞肺癌的发生发展中发挥作用。