Patients with CBF-AML are consistently cytarabine-anthracycline responders with favorable outcomes (Table 2). The substantial heterogeneities observed in the outcome of CBF-AML patients are associated with the co-occurrence of other mutations occurred in specific genes, eg, FLT3, KIT and RAS (Figure 2 & Table 2). Therefore, for right diagnosis and proper management of the cancer, specific mutations occurred in FLT3, NPM1, CEBPA, RAN, and KIT genes should be taken into account, besides the cytogenetic alterations.3,15,10

The t(15;17)(q22;q12) is classified as a balanced translocation which fusing the retinoic acid receptor-α (RARA) gene on chromosome 17(q21) with the PML gene on chromosome 15(q24) and leading to the expression of oncogene PML-RARA in hematopoietic myeloid cells. In patients with acute promyelocytic leukemia (APL), the presence of the PML-RARA rearrangement predicts a favorable response to treatment with retinoic acid (RA). APL accounts for about 10–15% of AML cases. The t(15;17)(q24;q21) and its fusion protein PML-RARα are present in about 98% of APL cases, accounted as the biomarker of APL.1–3

Notably, low-risk APL patients can attain 100% complete remission (CR) and 2-year event-free survival (EFS) of 97%, just by a combination of arsenic trioxide and all-trans retinoic acid (ATRA), with no additional chemotherapy. Now, ATRA is considered as a proper treatment of leukemia or as a part of remission induction therapy, both in adults and in children.8,10 RARα is a member of the nuclear hormone-receptor superfamily, which activating transcription in the presence of retinoic acids (RAs) (ATRA or 9-cis retinoic acid, CTRA) and inducing many target genes required for the hematopoietic differentiation.5,6 At the molecular level, RARα and retinoid X receptor-α (RXRα) form the heterodimer RAR-RXR that binds DNA at retinoic acid-response elements (RARE). RAR-RXR forms a transcription activator complex required for promyelocytic differentiation. In the absence of RAs, RAR-RXR heterodimer acts as a transcription repressor by recruiting corepressors DNMT1, DNMT3A, histone deacetylases (HDACs) and histone methyltransferases, all of which remodeling chromatin. In the presence of RAs, conformational changes occur in RAR-RXR, whereby causing dissociation of co-repressor complexes from RAR-RXR, and transcriptional de-repression and activation of genes required for the differentiation of promyelocytes.6,8

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PML-RARA competes with RARα to form a heterodimer with RXRα, then represses target promoters of the signaling chain in the same manner as RARA when it is not bound to its ligand. However, unlike the wild variant, it requires a greater concentration of ligand to eliminate the repression because it maintains a more stable interaction with the corepressor complex and some methylases such as DNMT1 and DNMT3A. Furthermore, PML-RARA has important effects on apoptosis because in a negatively dominant manner it interferes with the function of wild PML and its regulation of p53.15,10 The pharmacological concentrations of ATRA can activate transcription by inducing dissociation of corepressors from PML-RARα which is then degraded by a proteasome-dependent manner. Immature leukemic promyelocytes require ATRA to differentiate into mature granulocytes wherein bypassing the co-repressor activity of PML-RARα and differentiating into the myeloid lineage.1,3 There are t(15;17) variants that all lead to the formation of PML-RARA fusion genes and occur in AML, but are absent in patients with other leukemia types. To detecting this translocation successfully, the RT-PCR and FISH are reliable techniques that link approaches to a favorable prognosis (Table 1). Notably, the PML locus in 15(q24) encodes transcripts through alternative splicing generating more than 20 different tumor-suppressor isoforms. These tumor suppressors participate in nuclear structures called the PML-nuclear bodies (PML-NBs) which sequestrates and release proteins from the nucleus. PML-NBs mediate posttranslational modifications and promote nuclear events in response to cellular stressors.5,6

The balanced translocation; t(9;22)(q34;q11) occurs between chromosomes 9 and 22, and produces the fusion oncogene BCR-ABL1. The 3ʹ-sequences of proto-oncogene ABL, a tyrosine kinase on chromosome 9, is fused to the 5ʹ-sequences of the BCR, a gene on chromosome 22. This translocation leads to the formation of Philadelphia chromosome (Ph) generally occurring in childhood ALL and chronic myelogenous leukemia (CML). Predominantly, the Ph+ chromosome causes an early B-cell phenotype. The Ph+ patients are mostly adolescence or young adulthood, usually older than 10 years, who show elevated leukocyte counts and frequently central nervous system (CNS) disease. The Ph + chromosome may occur late as a secondary aberration in CML, B-ALL, T-ALL, and primarily AML. There are two variants of the BCR-ABL1 oncogene, “minor” (m-bcr, encoding p190 kDa protein) and “major” (M-bcr, encoding p210 kDa protein), as a result of two different breakpoint in cluster regions of the BCR gene. The interphase FISH, RT-PCR, or RQ-PCR methods are reliable techniques to detect this rearrangement (Table 1).6,15,10

The mixed-lineage myeloid/lymphoid leukemia (MLL) gene is mapped to 11q23 covering a genomic DNA region of approximately 100 kb. The chromosomal rearrangements at 11q23 include translocations, deletions, and duplications. The 11q23 rearrangement most often results in gene hybridization between the 5ʹ-sequences of the MLL gene and the 3ʹ-sequences of the other partner gene. Exons 5–11 on 11q23, cluster the majority of breakpoints, in a region extended about 8.3 kb long.8,10

The hybrid proteins harbor the N-terminal residues of MLL and the C-terminal residues of the partner protein. The hybrid proteins localize in the nucleus of the hematopoietic stem cell wherein exhibiting transforming activity. MLL is a master regulator of hematopoiesis in hematopoietic stem cells wherein regulating the homeobox genes (HOX). This group of genes consecutively influences hematopoietic stem-cell renewal and leukemogenesis. In addition to mixed-lineage leukemia, the rearrangement also occurs in myeloid and lymphoid leukemic cells, thereby exhibiting its origination from a stem cell or an early progenitor cell. The prognostic significance of 11q23 abnormalities has been variably assigned between intermediate-risk and adverse-risk groups (Tables 1 and 7).1,2

The most common genetic events occurring in ALL or AML children aged <12 months are the MLL rearrangements. It is dominant in 43–58% of infants aged less than 12 months, in 39% of children aged between 13 and 24 months, and in 8-9% of children who older than 24 months. Generally, the chance of MLL rearrangement decreases with age where it has 4 times more incidence in children than in adults (Figure 4). Approximately 5-10% of MLL rearrangements occur as a secondary event or therapy-related leukemia that arise in patients treated with topoisomerase II inhibitors for other malignancy.3

MLL is a large protein with multi-domains and DNA-binding activity interacting directly with DNA and other DNA-binding proteins. As a histone methyltransferase belonging to the trithorax-group family, hematopoietic cells including stem and progenitor populations ubiquitously express MLL. The fusion protein binds DNA constitutively and sequentially activates HOX genes such as HoxA9 and HoxA10 which commonly up-regulated in leukemia. At the molecular level, MLL participates to methylate histone H3 on lysine residue 4 (H3K4), which positively regulates gene expression in embryogenesis and hematopoiesis.6

Profoundly, MLL gene fusion to a wide array of partner genes, including AF4, AF9, ENL, AF10 and ELL has leukemogenic effects. MLL rearrangements involve several partner genes including t(6;11)(q27;q23), in which MLL is fused to AF6; t(9;11)(p22; q23), in which MLL is fused with AF9; and t(10;11)(p12;q23), in which MLL (on 11q, the long arm of chromosome 11) is fused to AF10 or MLLT10 (on 10p, the short arm of chromosome 10). MLL-AF10, MLL-ABI1, and CALM-AF10 are fusion genes identified in leukemic patients with t(10;11)(p12;q23). The MLL fusion proteins attain a dominant gain-of-function trait enhancing the transcriptional activity and giving rise to the poor prognosis of patients with MLL translocations. Herein, RT-PCR method is a reliable technique to identify these subtle translocations, besides cytogenetic analysis. The fusion transcripts are readily detectable by RT-PCR, which is especially useful in tracking the minimal residual disease. Southern blotting with cytogenetic analysis is able to detect the majority of MLL rearrangements and iFISH in a complementary fashion for the accurate identification of MLL status.15,10

Patients with 11q23 rearrangements (MLL mutations) show intermediate to the adverse prognosis that depends on the second or partner genetic aberrations (Table 1). The 11q23 rearrangement with the partner t(9;11)(p22;q23) shows a more favorable prognosis that places it in the intermediate group (Tables 1 and 7). Patients with 11q23 rearrangements have an intermediate response to conventional chemotherapy (the combination of an anthracycline and HDAC for induction, then 1–2 cycles of HDAC-based consolidation followed by HSCT) (Tables 1 and 2).6,15,10

The hybrid gene OTT-MAL is a result of t(1;22)(p13;q13) translocation occurring mainly in young children, especially in those younger than 24 months, and is highly correlated with acute megakaryoblastic leukemia (AML M7). The strong correlation existing between t(1;22) and AML M7 implies that there is an existence of prenatal genetic factors involved in the incidence of this particular form of disease. Specifically, this translocation occurs primarily in girls and exhibits an inferior outcome.6,15

The meningioma 1 (MN1) gene, localized on human chromosome 22, is disrupted by the balanced translocation t(12;22) which results in the fusion protein TEL-MN1. Incooperation with HOXA9, TEL-MN1 promotes the growth of primitive HPCs. HOXA9 is over-expressed in AML. MN1 as a unique oncogene involving in hematopoiesis participates in both aspects of self-renewal; by promoting proliferation and blocking differentiation. The MN1 expression level is a predictive marker in AML treatment, wherein MN1 high-expression levels correlate with resistance to ATRA treatment. These predictive levels are particularly important in elderly patients.8

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