Cloning and developmental expression of the murine homolog of the acute leukemia proto-oncogene AF4

Baskaran, K.; Erfurth, Frank; Taborn, Greg; Copeland, Neal G.; Gilbert, Debra J.; Jenkins, Nancy A.; Iannaccone, Philip M.; Domer, Peter H.

doi:10.1038/sj.onc.1201365

Cited by 26 publications

(18 citation statements)

References 34 publications

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“…loss of AF5q31 does not cause a complete and uniform block of embryogenesis at a given point but that AF5q31 possesses versatile roles during embryogenesis. Since AF5q31 and AF4 are widely expressed during embryogenesis and in the adult tissues of mice, it is possible that AF4 functionally compensates for the lack of AF5q31 in most tissues (4,33). Presently, it is unclear why the embryonic and neonatal death occurs and whether the incomplete penetrance of this phenotype results from heterogeneity in the genetic background of the mutant mice.…”

Section: Mechanism Of Infertility In Af5q31mentioning

confidence: 91%

Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia

Urano

Endoh

Morikawa

et al. 2005

Molecular and Cellular Biology

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AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.Chromosomal translocation is one of the common pathogenic mechanisms in various human malignancies, particularly in leukemias and lymphomas, and genes located at the breakpoints are involved in disease pathogenesis (21,59,60). The mixed lineage leukemia gene MLL (also called HRX, HTRX, and ALL-1) is frequently targeted by chromosomal rearrangements and is associated with clinically aggressive lymphoid and myeloid leukemias which are particularly prevalent in infant leukemias and treatment-related secondary leukemias (2,18,24,64). MLL located on 11q23 is a human homologue of Drosophila trithorax, has a SET domain that normally functions as histone methyltransferase, and is assembled into a supermultiprotein complex with additional chromatin-remodeling components (45,50,70). Importantly, most of the leukemic variants of MLL lack the SET domain (7). In Drosophila, genetic evidence suggests that Trithorax controls the expression of homeobox (Hox) genes and regulates embryogenesis (39,44,47). In MLL-deficient mice, Hox gene expression initiates normally but is not maintained after 9.5 days postcoitus (dpc), demonstrating the importance of MLL in the maintenance of Hox gene expression (72,73). Hox genes also play an important role in hematopoietic differentiation, and their expression levels are upregulated in the human leukemias carrying MLL rearrangements (1). An unusual feature of MLL fusion proteins is the large number and diversity of heterologous proteins that fuse with MLL. To date, the MLL locus has been found to be translocated to approximately 40 different genetic loci and at least 30 of the partner genes have been characterized (13,31). The fun...

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Section: Mechanism Of Infertility In Af5q31mentioning

confidence: 91%

Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia

Urano

Endoh

Morikawa

et al. 2005

Molecular and Cellular Biology

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“…AF4 is a member of a protein family containing FMR2, LAF4, and AF5q31, which are all nuclear proteins with transactivation activity, suggesting that they act as transcription factors (Prasad et al, 1995;Gu et al, 1996;Ma and Staudt, 1996;Baskaran et al, 1997;Gecz et al, 1997;Nilson et al, 1997;Isnard et al, 1998;Li et al, 1998;Taki et al, 1999). In addition, it has been demonstrated that LAF4 has nonspecific DNA binding properties (Ma and Staudt, 1996).…”

Section: Discussionmentioning

confidence: 99%

A Mutation inAf4Is Predicted to Cause Cerebellar Ataxia and Cataracts in the Robotic Mouse

et al. 2003

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The robotic mouse is an autosomal dominant mutant that arose from a large-scale chemical mutagenesis program. It has a jerky, ataxic gait and develops adult-onset Purkinje cell loss in the cerebellum in a striking region-specific pattern, as well as cataracts. Genetic and physical mapping of the disease locus led to the identification of a missense mutation in a highly conserved region of Af4, a putative transcription factor that has been previously implicated in leukemogenesis. We demonstrate that Af4 is specifically expressed in Purkinje cells, and we hypothesize that the expression of mutant Af4 leads to neurodegeneration. This function was not identified through knock-out studies, highlighting the power of phenotype-driven mutagenesis in the mouse to identify new pathways involved in neurological disease.

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“…It has been suggested that af4 plays an important role in the development of the hematopoietic, cardiovascular, and skeletal and central nervous systems and the disruption of normal af4 function by the translocation may contribute to leukemogenesis. (Baskaran et al, 1997). Yamamoto et al suggest that the instability of the af4 gene may be associated with the leukemogenesis of infant leukemia (Yamamoto et al, 1998).…”

Section: R Esults and Discussionmentioning

confidence: 99%

Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemia t (15;17)patients

Savlı

Sırma²,

Nagy³

et al. 2004

Exp Mol Med

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Cloning and developmental expression of the murine homolog of the acute leukemia proto-oncogene AF4

Cited by 26 publications

References 34 publications

Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia

Infertility with Defective Spermiogenesis in Mice Lacking AF5q31, the Target of Chromosomal Translocation in Human Infant Leukemia

A Mutation inAf4Is Predicted to Cause Cerebellar Ataxia and Cataracts in the Robotic Mouse

Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemia t (15;17)patients

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