*3.1.3 The KMT2A (MLL) Gene Rearrangements (11q23)*

A transcriptional coactivator with methyltransferase activity encodes the gene KMT2A. The rearrangements result in the fusion of the 5′ portion of KMT2A, including the methyltransferase domain, to the 3′ region of the partner genes.

KMT2A (MLL) rearrangements, particularly the translocation of t(4;11)(q21;q23), are most common in infants (<1 year of age) and are associated with poor outcomes [23, 24]. The t(4;11)(q21;q23) can be detected by conventional cytogenetics, FISH, RT-PCR, or Southern blot techniques. Overall, ALL with MLL rearrangement have an unfavorable prognosis.

### *3.1.4 The t(1;19)(q23;P13), TCF3-PBX1*

The translocation t(1;19)(q23;p13) is the result of the fusion of the PBX1 gene at 1q23 with the TCF3 (E2A) gene at 19p13.3. This translocation occurs in approximately 5–6% of childhood and adult B-cell precursor (BCP) ALLs [25, 26]. The translocation t(1.19) appears in balanced form (presence of two derived chromosome) or more often in unbalanced form with the derivative chromosome 19: (der (19)t(1.19) (q23;p13)). TCF3-PBX1 patients usually have a pre-B immunophenotype that expresses cytoplasmic μ [27]. It's one of the few genetic disorders that doesn't seem to increase in frequency with age. Originally considered a high-risk subtype of ALL, it is now associated with a favorable outcome with contemporary treatment, although some studies have indicated that it has an independent risk factor for CNS relapse [28].

## *3.1.5 IKZF1(7p12) deletion or mutations*

The IKZF1 gene is located on the 7p12.2 chromosome band, consists of 8 exons, and codes for the transcription factor IKAROS with key regulatory functions in lymphopoiesis [29, 30]. IKAROS harbors 6 fingers zinc. Four of these are located in the DNA-binding domain encoded by exons 4 to 6 and are important for the tumor suppressor function of IKAROS to be preserved. Exon 8 encodes the remaining 2 zinc fingers and mediates IKAROS dimerization either as a homodimer or with other transcription factors in its family [29, 31]. The deletions of this gene, are very frequently associated with the BCR-ABL1 fusion in the development of ALL of the B line. These deletions result in haploinsufficiency by partial or total deletion. it seems that these deletions represent an independent risk of relapse.

#### *3.1.6 CRLF2 rearrangement (IGH-CRLF2; P2RY8-CRLF2)*

CRLF2 encodes cytokine receptor-like factor 2, also known as the thymic stromal-derived lymphopoietin receptor (TSLPR), wich forms an heterodimeric receptor with the interleukin-7 receptor a chain (IL7Ra) for thymic stromal lymphopoietin (TSLP). CRLF2 is deregulated by translocation into the immunoglobulin heavy chain locus (IGH-CRLF2); focal deletion upstream of CRLF2, resulting in P2RY8-CRLF2 fusion; and less often, CRLF2 point mutations (F232C) [32]. In Ph-like and Down syndrome-related ALL, CRLF2 rearrangements are most common and are age dependent, with P2RY8-CRLF2 associated with young age and IGH-CRLF2 associated with older age and Hispanic ancestry [33, 34]. Most CRLF2-rearranged ALLs have additional JAK–STAT or Ras signaling alterations, particularly activating JAK1 or JAK2 mutations, FLT3 and IL7R sequence mutations, SH2B3 deletions, TSLP rearrangements, and Ras mutations [35–37]. CRLF2 rearrangements have been associated with poor prognosis in most studies, especially in cases of concomitant IKZF1 alteration [38, 39].

#### *3.1.7 Intrachromosomal amplification of chromosome 21 (iAMP21)*

Intrachromosomal amplification of chromosome 21 or iAMP21 is defined as the presence of three or more additional copies of *RUNX1* on a structurally

**107**

*Genetic Abnormalities in ALL*

*(Ph-like ALL)*

**3.2 ALL with number anomalies**

*3.2.1 Hyperdiploidy*

*3.2.2 Hypodiploidy*

*DOI: http://dx.doi.org/10.5772/intechopen.97429*

determining the best course of treatment.

abnormal chromosome 21. The iAMP21 chromosome is often initially detected by *ETV6* - *RUNX1* FISH analysis [40, 41]. It affects about 2–5% of B-cell precursor acute lymphoblastic leukemia pediatric patients [42, 43]. Patients with iAMP21 are usually between the ages of 7 and 13, with a median age of 10 [44]. It is particularly uncommon in children under the age of five and in people over the age of twenty. Complex intrachromosomal amplification of chromosome 21 is most common in older children and the poor prognosis is improved by high-risk treatment. Accurate identification of this abnormality is considered to be extremely necessary in

*3.1.8 The Philadelphia Chromosome – like Acute Lymphoblastic Leukemia* 

minimal residual disease (MRD), and/or poor survival [48].

loidy is associated with trisomies of chromosomes 4 and 10 [52–54].

Ph-like, or BCR-ABL1-like ALL is characterized by a leukemic cell transcriptional profile similar to Ph + ALL but lack the BCR-ABL1 fusion gene [45, 46]. Ph-like ALL is vary heterogeneous in the altered genes and the form (rearrangements, mutations, or deletions) of alterations that result in the activated tyrosine kinase or cytokine receptor signaling characteristic of this subtype of ALL [46]. However, these fall into four main groups: (1) Alterations driving JAK–STAT signaling, most commonly rearrangements of CRLF2 (IGH-CRLF2, P2RY8-CRLF2, CRLF2 F232C), and less commonly, rearrangements of JAK2, EPOR, or TYK2, and mutations/deletions of IL7R, SH2B3, JAK1, JAK3, TYK2, IL2RB); (2) fusions involving ABL-class genes (ABL1, ABL2, CSF1R, LYN, PDGFRA, PDGFRB); (3) mutations activating Ras signaling (NRAS, KRAS, PTPN11); and (4) less common fusions (FLT3, FGFR1, NTRK3) [35, 36, 47]. Ph-like is associated with high-risk clinical characteristics, poor response to induction chemotherapy, elevated levels of

Hyperdiploidy is the most prevalent recurrent abnormality in childhood B-ALL. In the World Health Organization classification of tumors of hematopoietic and lymphoid tissues, hyperdiploidy in B-lymphoblastic leukemia (B-ALL), characterized by the presence of 51–65 chromosomes, has been identified as a distinct subtype of B-ALL [49]. In hyperdiploidy, numerical chromosomal gains are nonrandom, with additional copies (usually trisomies) of chromosomes 21, X, 14, and 4 most commonly found in pediatric patients [50]. Despite the presence of nonspecific structural abnormalities, the extra chromosomes are still normal copies of chromosomes. There is a poor understanding of the mechanism involved in inducing hyperdiploidy and its role in leukaemogenesis. Hyperdiploid B-ALL comprises approximately 25–30% of pediatric B-ALL cases [51]; and is often associated with a favorable prognosis with a cure rate greater than 90%, especially when hyperdip-

Hypodiploidy, characterized by less than 44 chromosomes is less frequent than hyperdiploid ALL. Three cytogenetic subgroups of hypodiploidy were defined: near haploidy, with 24–31 chromosomes; low hypodiploid, with 32–39 chromosomes; and high hypodiploid, with 40–43 chromosomes [55]. Near-haploidy patients showed common chromosomal gains, rare structural abnormalities and a

#### *Genetic Abnormalities in ALL DOI: http://dx.doi.org/10.5772/intechopen.97429*

abnormal chromosome 21. The iAMP21 chromosome is often initially detected by *ETV6* - *RUNX1* FISH analysis [40, 41]. It affects about 2–5% of B-cell precursor acute lymphoblastic leukemia pediatric patients [42, 43]. Patients with iAMP21 are usually between the ages of 7 and 13, with a median age of 10 [44]. It is particularly uncommon in children under the age of five and in people over the age of twenty. Complex intrachromosomal amplification of chromosome 21 is most common in older children and the poor prognosis is improved by high-risk treatment. Accurate identification of this abnormality is considered to be extremely necessary in determining the best course of treatment.
