ML-1 cell line lacks a germlineMLL locus

Strout, Matthew P.; Mrózek, Krzysztof; Heinonen, Kristiina; Sait, Sheila N.J.; Shows, Thomas B.; Aplan, Peter D.

doi:10.1002/(sici)1098-2264(199607)16:3<204::aid-gcc8>3.0.co;2-2

Cited by 12 publications

(8 citation statements)

References 22 publications

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“…The chromosomal breakpoint of a patient with a therapy-related AML and translocation t(6;11) can be interpreted in a similar manner (Figure 6; Strout et al, 1996). Severe DNA damage probably occurred as a consequence of the chemotherapeutic treatment.…”

Section: Isolation Of Breakpoint Amplimers For Three T(4;11) Cell Linesmentioning

confidence: 86%

Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation

et al. 1998

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Chromosomal translocations t(4;11) are regularly associated with a speci®c type of acute leukemias and probably initiate the development of this disease. It has been proposed by others, that these translocations are mediated by recombinases of the immune system. The breakpoints on both derivative chromosomes for three t(4;11) leukemia-derived cell lines and primary blasts from two patients have been analysed here in detail. The results revealed that: (a) multiple double-or singlestranded DNA breaks must have occured near the translocation breakpoints on both participating chromosomes; and (b) DNA fragments¯anked by these breaks must have either been deleted, inverted or duplicated during the translocation process. We found no evidence for the involvement of speci®c target sequences and recombinases of the immune system. Similar characteristic features were observed by re-interpretation of published t(6;11) and t(9;22) translocation data. Therefore we present a new model for the generation of these translocations which poses, that these translocations are reciprocal but not balanced at the ®ne structure level and that the DNA damage-repair machinery is likely involved in producing the ®nal structure of the translocation breakpoint.

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Section: Isolation Of Breakpoint Amplimers For Three T(4;11) Cell Linesmentioning

confidence: 86%

Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation

et al. 1998

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“…Although both the der(11) and der(4) genomic breakpoint junctions have been amplified with gene-specific primers in many de novo leukemias with t(4;11) (4, 5), both genomic breakpoint junctions have been characterized in few de novo leukemias with other MLL translocations (6) and few leukemias after chemotherapy with DNA topoisomerase II inhibitors (7,(21)(22)(23). As in the ALL of patient 45, the sequences in de novo cases have shown regions up to several hundred bases from MLL and͞or the partner gene on both derivative chromosomes, suggesting duplication (4-6).…”

Section: Discussionmentioning

confidence: 99%

Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions ofMLLtranslocations and identify complex translocation ofMLL,AF-4, andCDK6

Raffini

Slater

Rappaport

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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We used panhandle PCR to clone the der(11) genomic breakpoint junction in three leukemias with t(4;11) and devised reversepanhandle PCR to clone the breakpoint junction of the other derivative chromosome. This work contributes two elements to knowledge on MLL translocations. First is reverse-panhandle PCR for cloning breakpoint junctions of the other derivative chromosomes, sequences of which are germane to understanding the MLL translocation process. The technique revealed duplicated sequences in one case of infant acute lymphoblastic leukemia (ALL) and small deletions in a case of treatment-related ALL. The second element is discovery of a three-way rearrangement of MLL, AF-4, and CDK6 in another case of infant ALL. Cytogenetic analysis was unsuccessful at diagnosis, but suggested t(4;11) and del(7)(q21q31) at relapse. Panhandle PCR analysis of the diagnostic marrow identified a breakpoint junction of MLL intron 8 and AF-4 intron 3. Reverse-panhandle PCR identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. CDK6 encodes a critical cell cycle regulator and is the first gene of this type disrupted by MLL translocation. Cdk6 is overexpressed or disrupted by translocation in many cancers. The in-frame CDK6-MLL transcript is provocative with respect to a potential contribution of the predicted Cdk6-MLL fusion protein in the genesis of the ALL, which also contains an in-frame MLL-AF4 transcript. The sequences in these three cases show additional MLL genomic breakpoint heterogeneity. Each breakpoint junction suggests nonhomologous end joining and is consistent with DNA damage and repair. CDK6-MLL is a new fusion of both genes.

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“…In these cells, one MLL allele is involved in a t(6;11)(q27;q23) chromosomal translocation that results in the expression of a chimeric MLL-AF6 protein, whereas the other MLL allele is deleted. 39 Intact MLL-AF6, but not normal MLL, was expressed in ML-1 cells ( Figure 1C, lane 2). Similarly, no processing of MLL-p300 was observed in BOSC23 cells that were transfected with an MLL-p300 expression construct ( Figure 1D, lane 3), although endogenous MLL N was detected.…”

Section: Mll Is Proteolytically Processed In Vivomentioning

confidence: 98%

Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties

Yokoyama

Kitabayashi

Ayton

et al. 2002

Blood

150

129

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MLL (mixed lineage leukemia; also ALL-1 or HRX) is a proto-oncogene that is mutated in a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. Here we demonstrate that MLL (mixed lineage leukemia) is proteolytically processed into 2 fragments (MLL N and MLL C ) that display opposite transcriptional properties and form an intramolecular MLL complex in vivo. Proteolytic cleavage occurs at 2 amino acids (D2666 and D2718) within a consensus processing sequence (QXD/GZDD, where X is a hydrophobic amino acid and Z is an alanine or a valine) that is conserved in TRX, the Drosophila homolog of MLL, and in the MLL-related protein MLL2, suggesting that processing is important for MLL function. Processed MLL N and MLL C associate with each other via N-terminal (1253-2254 amino acids) and C-terminal (3602-3742 amino acids) intramolecular interaction domains. MLL processing occurs rapidly within a few hours after translation and is followed by the phosphorylation of MLL C . MLL N displays transcriptional repression activity, whereas MLL C has strong transcriptional activation properties. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLL C . These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions. (Blood. 2002;100:3710-3718)

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ML-1 cell line lacks a germlineMLL locus

Cited by 12 publications

References 22 publications

Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation

Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation

Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions ofMLLtranslocations and identify complex translocation ofMLL,AF-4, andCDK6

Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties

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