Pediatric biphenotypic acute leukemia

Suggested involvement of a pluripotent stem cell.

De novo acute leukemia.

The only case described was a 6-year-old boy who was diagnosed as having biphenotypic phenotype (T/myeloid) acute leukemia (Cerveira et al., 2010). This is the first, and to our knowledge, the only case described in the literature of a rearrangement between the CT45A2 gene located on Xq26.3 and the MLL gene located in 11q23 (Cerveira et al., 2010).

Fever, asthenia and cutaneous pallor. Peripheral blood analysis revealed anemia (Hb 6,3 g/dl) and bicytopenia. Bone marrow analysis revealed the presence of 51% of blasts with the immunophenotype CD3+, CD13+, CD33+, and CD117+. No blasts were detected in the cerebrospinal fluid (Cerveira et al., 2010).

In the only case characterized the karyotype was complex showing a cryptic insertion of 11q23, where the MLL gene is located, in Xq22~25 (Cerveira et al., 2010). Based on the chromosome banding and FISH findings, the karyotype was described as 45,XY,add(14)(q24),add(17)(p13),-18[8].ish ins(X;11)(q22~25;q23q23)(MLL5+;MLL5-,MLL3+), add(14)(IGH-),der(17)(17qter-->17p13::?::18q21-->18q21::?)(BCL2+)/46,XY[12].

The patient was treated according to the ELAM 02 protocol (aracytine, mitoxantrone and methotrexate) and entered complete remission after induction chemotherapy. Seven months later he was submitted to allogeneic bone marrow transplantation with umbilical cord hematopoietic progenitors but, after one year, the patient showed evidence of relapse. Treatment with the AML relapse protocol was started, but only partial remission was achieved four months later. The patient underwent a haploidentical transplant with his mothers peripheral blood cell progenitors, but the disease relapsed again and the patient died nine months later. In conclusion, the prognosis seems to be rather poor, but additional cases are needed to support this hypothesis.

5 MLL - 3 CT45A2
The in-frame fusion is predicted to give rise to a chimeric protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2 (Cerveira et al., 2010). The putative MLL-CT45A2 fusion protein of 1514 amino acids contains 1325 amino acids from the N-terminal portion of MLL and 189 amino acids deriving from the CT45A2 protein (Cerveira et al., 2010).

5-MLL/CT45A2-3 chimeric transcript.
The MLL exon 9 is fused in-frame with nucleotide 240 of the CT45A2 transcript. This fusion transcript contains 6 bp from the 5-UTR of CT45A2 exon 2 coding for two additional amino acids (Cerveira et al., 2010). This type of fusion is known as a spliced fusion since the chimeric MLL-CT45A2 is only generated at the RNA level and can occur either by transcriptional read-through followed by a subsequent splice event or by trans-splicing. Regardless of the underlying mechanism, the chimeric MLL-CT45A2 fusion is only produced at the RNA level (Cerveira et al., 2010).

MLL fusion genes codes for chimeric proteins that reside in the nucleus (Marschalek, 2011).

Deregulation of MLL protein activity result in abnormal patterns of target genes expression, including genes from the HOX family (Cerveira et al., 2011; Marschalek, 2011). HOX genes are normally expressed in lineage- and stage-specific combinations during hematopoiesis; however, cell commitment to myeloid or erythroid lineages is accompanied by global downregulation of HOX gene expression (Cerveira et al., 2011; Marschalek, 2011). A failure to downregulate HOX expression can inhibit hematopoietic maturation and lead to leukemia. However, it seems that the leukemia phenotype also depends on the fusion partner, indicating that, at least for some fusion partners, the gene involved is critical for leukemogenesis. A consequence of this fusion is that the expression of the CT45A2 protein, usually restricted to testicular tissue, is activated. The phenotypic consequences of CT45A2 expression in the leukemia cells of leukemia patients are currently unknown (Cerveira et al., 2010).