Disease relevance of MLLT10

• MLL-MLLT10 fusion in acute monoblastic leukemia: variant complex rearrangements and 11q proximal breakpoint heterogeneity [1].
• AF10 is involved in 2 distinct chromosomal translocations associated with hematologic malignancy [2].
• The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10 [3].
• The recurrent t(10;11)(p13;q14) translocation, usually found in acute myeloid leukemia (AML) and T-ALL, merges PICALM to MLLT10 [4].
• Fluorescence in situ hybridization studies have demonstrated that AF10 and CALM are also involved in other hematological malignancies containing t(10;11)(p13;q21), but no data are available concerning the molecular details of AF10-CALM fusion in primary leukemias [5].

High impact information on MLLT10

• RNA was examined from fresh human B cells stimulated to IgE production by interleukin 4 plus anti-CD40, as well as from the human IgE-producing line AF10 [6].
• Using a combination of positional cloning and candidate gene approach, we cloned the breakpoint and were able to show that AF10 is fused to a novel gene that we named CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene) located at 11q14 [7].
• AF10, a putative transcription factor, had recently been cloned as one of the fusion partners of MLL [7].
• The identification of the CALM/AF10 fusion gene in the widely used U937 cell line will contribute to our understanding of the malignant phenotype of this line [7].
• The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family [7].

Biological context of MLLT10

• 10;11 rearrangements require at least three breaks in order to generate an in-frame MLL-MLLT10 fusion as a result of the opposite orientations of both genes on the respective chromosome arms [8].
• We observed an as yet unreported chromosomal mechanism with at least four breakpoints, leading to MLL-MLLT10 gene fusion in a 24-year-old male [8].
• In this study, we describe a detailed molecular cytogenetic analysis of MLL-MLLT10 positive 10;11 rearrangements in two patients [8].
• The AF10 gene encodes a putative transcription factor containing an N-terminal LAP/PHD zinc finger motif, a functional nuclear localization signal, an AT-hook domain, and a leucine zipper toward the C-terminus [2].
• Interphase fluorescence in situ hybridization (FISH) was performed with 2 YACs flanking the CALM region, a YAC contig of the MLL region, and a YAC spanning the AF10 breakpoint [9].

Anatomical context of MLLT10

• We recently cloned CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene), the fusion partner of AF10 at 11q14 in the monocytic cell line U937 [9].
• Using RT-PCR, we amplified multiple different isoforms of AF10-CALM and CALM-AF10 fusion cDNAs from a primary T cell ALL containing a t(10;11)(p13-14;q14-21) [5].
• An identical clone with an in frame fusion of the MLL and AF10 genes was identified from both tissue and bone marrow samples [10].
• In 2/7 cases, FISH detected CALM/AF10 in extramedullary leukemic infiltrations in the mediastinum and breast [11].
• GH enhanced Ig production and thymidine uptake in the human plasma cell lines, IM-9 and AF-10 [12].

Associations of MLLT10 with chemical compounds

• The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10 [13].
• A consistent feature of these fusions was the juxtaposition of the leucine dimerization motif of AF10 onto the NH2-terminal region of HRX [14].
• However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper [15].
• The mutation was mapped to a Drosophila homolog of human AF10/AF17 leukemia fusion genes (alf), and therefore named Dalf [16].
• Using AF10 cells, whose growth was determined to be mediated by the autocrine action of IL-6, we found that RA reduction of IL-6R was concentration-dependent over a range of 10(-11) to 10(-5) M and corresponded to the ability of the retinoid to inhibit cell proliferation [17].

Other interactions of MLLT10

• MLL and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with translocation t(10;11): both rearrangements are associated with a poor prognosis [9].
• Gene BR140, which is related to AF10 and AF17, maps to chromosome band 3p25 [18].
• MLL-MLLT10 fusion gene in pediatric acute megakaryoblastic leukemia [19].
• Reverse transcription-PCR analysis carried out in six patients showed a 5' MLL-3' AF-10 fusion transcript [20].
• Biochemical analyses of the AF10 protein: the extended LAP/PHD-finger mediates oligomerisation [21].

Analytical, diagnostic and therapeutic context of MLLT10

• We present two new pediatric cases (French-American-British type M5) with MLL-MLLT10 fusion, which we studied with fluorescence in situ hybridization [1].
• Breakpoint heterogeneity in t(10;11) translocation in AML-M4/M5 resulting in fusion of AF10 and MLL is resolved by fluorescent in situ hybridization analysis [20].
• A novel class of conserved transcription factors has been identified from the molecular cloning of AF10, the gene involved in the t(10;11)(p12;q23) translocation of acute myeloid leukemias [22].
• A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method [23].
• Sequence analysis revealed that all these isoforms had in-frame junctions and that some of them resulted from alternative splicing at different exons of CALM and others from different breakpoints at CALM and/or AF10 [24].

References