Original articleC/EBPβ suppression by interruption of CUGBP1 resulting from a complex rearrangement of MLL
Introduction
Translocations of chromosomal band 11q23 are among the most observed rearrangements in leukemia, occurring in 5–6% of primary acute myelogenous leukemias (AML), a majority of secondary leukemias, and nearly all infant acute lymphocytic leukemias (ALL) [1], [2]. 11q23 translocations disrupt the mixed-lineage leukemia (MLL) gene and usually confer a poor prognosis [1], [3]. The MLL gene is nonrandomly fused with one of several dozen MLL fusion partner genes such as AF4, AF6, ELL, and ENL[2], [4], [5], [6]. Most rearrangements of the MLL gene occur within a single 8.5-kb breakpoint cluster region and can be identified by cytogenetic G-banding and fluorescent in situ hybridization (FISH) analyses [6], [7], [8], [9], [10]. The t(1;11)(q21;q23) fuses the MLL gene to the AF1q gene located on chromosomal band 1q21 [6], [11]. To our knowledge, fewer than 20 cases of this translocation have been reported this past decade [5], [6], [11], [12].
CCAAT/enhancer binding proteins (C/EBPs) are transcription factors known to play a critical role in myeloid differentiation. They are often dysregulated in myeloid leukemias and have been identified as targets of BCR/ABL, ETO, and FLT3 mutations. Expression of C/EBP proteins is controlled at several levels, including regulation of translation by certain RNA-binding proteins. One of these proteins, CUG triplet repeat binding protein-1 (CUGBP1), is a translational regulator of C/EBPβ that interacts with the 5′ region of C/EBPβ mRNA and increases the translation of two C/EBPβ isoforms, liver-enriched activator protein (LAP) and liver-enriched inhibitory protein (LIP) [13].
In this case report, we describe a variant t(1;11)(q21;q23) occurring in a pediatric AML patient (designated AML17) that activates MLL as described previously, but also disrupts CUGBP1, leading to decreased translation of C/EBPβ.
Section snippets
Clinical history
The patient described herein (AML17) is a 7-month-old Hispanic female who presented to the local emergency room with a history of 1 week of upper respiratory symptoms, 2 days of fussiness, and fever to 40°C. The presenting white blood cell (WBC) count was 310 × 103 cells/μL with a morphology on peripheral smear suggestive of myeloblasts. Hydration reduced the WBC count to 210.6 × 103 cells/μL. A large-bore pheresis catheter was placed, and leukaphoresis was performed that reduced her WBC to
A variant t(1;11)(q21;q23) identified by cytogenetics and FISH
The rearrangement of chromosomal bands 1q21 and 11q23 was identified in the routine G-banding analysis (Fig. 1a). Metaphase FISH using region-specific probes for chromosome 1 shows normal 1p and 1q telomeric hybridization signals on one copy of chromosome 1 but only a 1p signal on the homologous chromosome. The remaining 1q signal is located on the derivative chromosome 11 (Fig. 1b). Similarly, metaphase FISH using region-specific probes for chromosome 11 shows normal 11p and 11q telomeric
Discussion
The germline MLL gene encodes a protein of 3,972 amino acids (431 kD), which is a common target for chromosomal translocations in acute leukemias [11], [17]. The human MLL gene is homologous to Drosophila trithorax, which is a homeotic transcriptional regulator and contains PHD finger motifs along with DNA-binding motifs such as AT hooks and a DNA methyltransferase homology region [11], [18], [19], [20]. Translocations involving the MLL gene form various in-frame fusion transcripts with many
Acknowledgments
We thank Dr. Deb Shardy for her technical help. This work was supported by research funding to W.T.C. from the American Society of Hematology (Research Trainee Award); to D.A.L. from the American Society for Clinical Oncology (Young Investigator Award), the For Julie Foundation, and the National Institutes of Health (R21 CA114251 and K12 CA90433); to R.M. from the Wilhelm-Sander-Foundation (grant 2001.061.2); and to N.A.T. from the National Institutes of Health (R01 CA100070).
W.T.C. performed
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