Curr Hematol Malig Rep (2012) 7:133–143 Gene name Genetic alteration Table 1 Novel recurring genetic alterations occurring in B-progenitor ALL and their correlation with outcome IKZF1 PAX5 CDKN2A/B CRLF2 JAK1/2 CREBBP iAMP21 TP53 Frequency ~80 % of BCR-ABL1 positive ALL; 15 % of pediatric B-ALL cases ~30 % of pediatric and adult B-ALL ~30 % of pediatric and adult B-ALL; 47 % of relapsed BCR-ABL1-ALL Up to 16 % of pediatric and adult B-ALL; >50 % Down syndrome ALL ~10 % of high-risk BCR- ABL1-like ALL and 18–35 % of Down syndrome ALL 19 % of relapsed B-ALL Up to 2 % in older children with B- ALL Prognosis Associated with poor outcome No association with outcome Associated with poor outcome in adult BCR-ABL1 positive ALL; controversial prognosis in other B-ALL subtypes Associated with poor outcome Associated with poor outcome Associated with glucocorticoid resistance Associated with poor outcome when patients are treated with standard therapy Associated with non-response to chemotherapy and poor event-free survival and overall survival rates Deletions or sequence mutations Deletions, sequence mutations or translocations Deletions Overexpression due to IGH@- CRLF2 or P2RY8-CRLF2 rearrangement or F232C mutation Sequence mutations Deletions and sequence mutation Intrachromosomal amplification Deletions and sequence mutations 12.4 % of B-ALL 135 References [5, 27–31] [17, 29, 35] [18 , 87, 88] [40–43] [40–43] [54 ] [50, 51] [56] such as lymphoid development (IKZF1, PAX5, EBF1, VPREB1), cell cycle regulation and tumor suppression (CDKN2A/CDKN2B, PTEN, BTG1, RB1), lymphoid signal- ing (BTLA, CD200), drug responsiveness (NR3C1), and DNA mismatch repair (MTOR, HERC1, PRKCZ, and PIK3C2B) [5, 15–17, 18 , 19, 20]. Importantly, there were substantial differ- ences in the frequency and nature of CNAs among various disease subtypes. MLL-rearranged leukemias harbor less than one CNA per case, suggesting that MLL is a potent oncogene that requires very few cooperating lesions to induce leukemia transformation. In contrast, ETV6-RUNX1 and BCR-ABL1 rearranged leukemias harbor six to eight alterations per case that may be present years after the initial chromosome rearrangements, indicating that these additional postnatal genetic alterations are required to induce the full leukemic phenotype [5]. Genetic Alterations in B-Lymphoid Development Genes Over two-thirds of genetic abnormalities affected genes involved in lymphoid development. These alterations in- clude deletions, focal amplifications, novel translocations, and point mutations involving transcriptional regulators of early B-cell lineage development, such as IKZF1 (Ikaros), PAX5 (Paired box 5), EBF1 (early B-cell factor), LEF1 (lymphoid enhancer factor 1), and immunoglobulin family genes, such as VPREB1 (pre-B lymphocyte 1). IKZF1 Ikaros is a DNA-binding zinc finger transcription factor that regulates the development and function of the immune system and acts as a master regulator of normal hematopoietic differentiation and proliferation, particularly in lymphoid lineages [21]. During the last 5 years, IKZF1 has been established as one of the most clinically relevant tumor suppressors in ALL. Deletion of a single IKZF1 allele or mutations of a single copy of IKZF1 were firstly detected in 15 % of all cases of pediatric B-cell ALL and in more than 80 % of Ph+lymphoid leukemia cases, either de novo Ph+ ALL or chronic myeloid leukemia at progression to lymphoid blast crisis [15, 22, 23]. By contrast, IKZF1 alter- ations were uncommon in other ALL subtypes that other- wise harbor multiple DNA copy-number alterations, such as ETV6-RUNX1 ALL, suggesting that IKZF1 alteration is a key determinant of the lineage and progression of Ph+ leukemia. The analysis of a twin pair concordant for ALL showed that in childhood Ph+ ALL, BCR-ABL1 gene fusion can be a prenatal and possibly initiating genetic event whereas deletion of IKZF1 is a secondary and probable postnatal mutation that is associated with poor prognosis [24]. The deletions either involve the entire IKZF1 lo- cus, resulting in loss of function, or delete an internal subset of IKZF1 exons, resulting in the expression of dominant negative IKZF1 alleles. Expression of such dominant negative IKZF1 alleles in hematopoietic pro- genitors impairs lymphoid development [25], and loss of IKZF1 accelerates the onset of Ph+ ALL in a retroviral