AF5q31 , a newly identified AF4 -related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23)

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by early pre-B phenotype (CD10 ؊ ͞ CD19 ؉ ) and poor treatment outcome. The t(4;11), creating MLL-AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with extremely poor prognosis as compared with other 11q23 translocations. We analyzed an infant early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on chromosome 5q31 as a fusion partner of the MLL gene. The AF5q31 gene, which encoded a protein of 1,163 aa, was located in the vicinity of the cytokine cluster region of chromosome 5q31 and contained at least 16 exons. The AF5q31 gene was expressed in fetal heart, lung, and brain at relatively high levels and fetal liver at a low level, but the expression in these tissues decreased in adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4, LAF4, and FMR2. The AF5q31 and AF4 proteins had three homologous regions, including the transactivation domain of AF4, and the breakpoint of AF5q31 was located within the region homologous to the transactivation domain of AF4. Furthermore, the clinical features of this patient with the MLL-AF5q31 fusion transcript, characterized by the early pre-B phenotype (CD10 ؊ ͞CD19 ؉ ) and poor outcome, were similar to those of patients having MLL-AF4 chimeric transcripts. These findings suggest that AF5q31 and AF4 might define a new family particularly involved in the pathogenesis of 11q23-associated-ALL.

Newly diagnosed acute lymphoblastic leukemia in China (I): abnormal genetic patterns in 1346 childhood and adult cases and their comparison with the reports from Western countries

“…Moreover, the regulation of these genes should be very complicated as some of them are only expressed at early stages (such as PAX5) in B-cell differentiation; 42,43 and others are downregulated with the growing of age (such as AFF4). 44 In contrast, in adult patients, the most frequent ones in B-ALL are t(9;22)/BCR --ABL that activates the tyrosine kinase signaling pathway, Ik6 variant of IKZF1 gene, and CRLF2 overexpression that is a cytokine receptor activating the JAK/STAT pathway. 14,15 Interestingly, CRLF2 overexpression and IKZF1 splicing deletion, which are significantly more involved in adults than in children, are both related to the poor outcome in B-ALL and closely associated with JAK mutations.…”

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

“…The mutation occurred in a highly conserved region of AF4, within a run of 13 amino acids that share 100% identity with all known AF4 homologs, suggesting that it plays a critical role in the function of the protein (Fig. 4) (Nilson et al, 1997;Taki et al, 1999;Britanova et al, 2002). No differences in expression level of any of the genes in the candidate region were observed between robotic and control animals by quantitative RT-PCR (data not shown).…”

“…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).…”

MLL fusion partners AF4 and AF9 interact at subnuclear foci

“…They can be loosely grouped into gene products which appear to be nuclear or cell surface proteins. There are subgroups of the fusion partners that come from common gene families such as AF4/AF5q31/LAF4, 13,14 ENL/AF9, 15 and AF10/AF17. 16 Owing to their lack of obvious biochemical similarity, the importance of the partner genes to leukemogenesis is unclear.…”

“…24,25 Gene knockout studies indicate AF4 plays an important role in B and T lymphopoiesis. 26 AF4 is a member of a gene family that includes two other ALL-associated MLL fusion partners, LAF-4 27,28 and AF5q31, 14 a putative Fragile X mental retardation gene FMR-2, 29 and the Drosophila melanogaster pair-rule gene lilliputian. 30 Genetic evidence suggests that lilliputian performs a partially redundant role in the Ras/MapK differentiation pathway.…”