136 bone marrow transplant and transgenic models of this disease [26]. Several studies demonstrated that IKZF1 deletions are significantly associated with an increased relapse rate and adverse events and are correlated with poor outcome in patients with Ph+ ALL [27–29]. Alter- ation of IKZF1 is also associated with poor outcome in BCR-ABL1-negative ALL [27, 29–31], where this asso- ciation is independent of commonly used risk stratifica- tion features such as age, sex, white cell count, and levels of minimal residual disease (MRD). IKZF1 dele- tions and nonsense mutations identified at diagnosis are preserved at relapse [27] and may be used for highly sensitive MRD tests in addition to the repertoire of MRD markers currently available for monitoring MRD in ALL [32]. Importantly, high-risk BCR-ABL1 negative ALL cases with deletion of IKZF1 and poor outcome have a gene expression profile significantly similar to that of Ph+ALL (“BCR-ABL1-like” ALL) [29, 33], sug- gesting that these cases may harbor alternative genetic events leading to aberrant activation of tyrosine kinase signaling pathways similar to those downstream of BCR-ABL1. PAX5 PAX5 encodes a transcription factor known as B-cell- specific activator protein, that plays a key role in B-cell commitment by activating essential components of B-cell receptor signaling and repressing the transcription of genes necessary for T-lymphopoiesis [34]. By SNP arrays mono- allelic deletion of PAX5 has been observed in about 30 % of both children and adults with B-ALL, resulting in loss of Pax5 protein expression or in the production of a Pax5 isoform lacking the DNA binding domain and/or transcrip- tional regulatory domain [5, 17]. Inactivating point muta- tions in PAX5 are also observed (7–30 %) as well as chromosomal translocations involving multiple partners such as ETV6, ENL, FOXP1, ZNF521, PML, C20ORF112, AUTS2, JAK2, POM121, HIPK1, DACH1, LOC392027, SLCO1B3, ASXL1, and KIF3B [5, 35, 36]. In these rear- rangements the DNA binding paired domain of PAX5 and/or a variable amount of the C-terminal trans-activating domains are fused to functional domains of the partner genes, resulting in a loss of Pax5 function rather than in a gain of functional elements. Alterations of PAX5 have been demonstrated to not influence treatment outcome [17, 29]. Genetic Alterations in Tumor Suppressors Genes CDKN2A/B The CDKN2A/B locus is particularly notewor- thy since it encodes for the INK4-class cyclin dependent kinase inhibitors p15INK4B, p16INK4A and for p14ARF, which inhibits MDM2’s E3 ligase activity stabilizing p53. Alter- ations have been demonstrated to frequently occur in all Curr Hematol Malig Rep (2012) 7:133–143 lymphoid malignancies, with homozygous deletions as the most frequent mechanism of inactivation [37]. Recently, we identified CDKN2A and CDKN2B deletion at diagnosis in 29 % and 25 % of BCR-ABL1-positive ALL patients, re- spectively. Deletions were predominantly monoallelic and in more than half of cases the minimal overlapping region of the lost area included a large number of genes. The detection rate of CDKN2A/ARF loss increased at relapse compared to diagnosis [18 ]. The association with prognosis is still con- troversial. Some studies reported a correlation of CDKN2A/ B deletion with poor prognosis, whereas others show no correlation [38]. Confirming previous findings from mice models [39], we demonstrated that deletions of CDKN2A/B are significantly associated with higher white blood count and poor outcome in terms of overall survival, disease-free survival, and cumulative incidence of relapse in adult BCR- ABL1-positive ALL [18 ]. Deregulated Expression of CRLF2 Four independent groups in late 2009 and early 2010 have identified that up to 50 % of BCR-ABL1-like ALL cases have dysregulated expression of CRLF2, the gene encoding the cytokine receptor-like 2 factor, also known as thymic stromal lym- phopoietin receptor [40–43]. CRLF2 has a role in T- lymphoid and dendritic cell development and is involved in inflammation and allergic responses [44]. Although it also mediates B-cell precursor proliferation and survival, its role in B-lymphoid neoplasms needs to be understood [45]. CRLF2 rearrangements include a translocation of CRLF2, which is located at the pseudoautosomal region 1 (PAR1) of chromosome Xp/Yp, into the immunoglobulin heavy chain locus at chromosome 14q or a focal PAR1 deletion proximal of CRLF2 that results in a novel fusion P2RY8-CRLF2 [40–43]. Less commonly, a mis- sense mutation in exon 6, F232C, results in constitutive CRLF2 dimerization [43]. All these events result in overexpression of full-length CRLF2 on the surface of leukemic cells harboring the genetic alterations, provid- ing a cell-surface marker amenable to detection by flow cytometry for clinical diagnostic purposes. Overall aber- rant expression of CRLF2 was found in 12.5 % to 15 % of B-ALL that lacks typical chromosomal rearrange- ments, but was not overexpressed in B-ALL cases that have recurring rearrangements or in other lymphoid malignancies [40–43]. CRLF2 alteration is seen at low rates (5–7 %) when all B-ALL cases are grouped to- gether; however, it is seen in 50–60 % of Down Syn- drome (DS) associated ALL, suggesting that CRLF2 overexpression is especially relevant to tumorigenesis in patients with trisomy 21 [41–43]. In high-risk B- ALL, rearrangements of CRLF2 are frequently found together with IKZF1 alterations and activating mutations in JAK1 and JAK2, most commonly at or near R683 in