**5. Conclusion**

290 Advances in Hematopoietic Stem Cell Research

regulating the B lineage-specific transcriptional program at an early stage (Durst & Hiebert, 2004). SNP array analysis of ETV6-RUNX1 samples has recently identified multiple additional genetic alterations, but the role of these lesions in leukemogenesis remains

Genome-wide analysis has recorded abnormalities in PAX5 and EBF1 in up to 32% of children and 30% of adults with B ALL, and in 35% of relapsed cases (Mullighan et al., 2007). Currently, five PAX5 fusions have been identified with the gene partners LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21) and C20orf112 (20q11.1), with the resulting chimeric proteins expressing lower levels of PAX5 and its target genes (An et al., 2008). EBF1 alterations are common in patients with poor outcomes and are

The MLL (mixed lineage leukemia) gene is often rearranged in leukemias with myeloid and lymphoid phenotype, probably indicating a very early multipotent progenitor origin. More than 50 fusions involving MLL have been documented. Among them, the MLL-AF4 [t(4;11)(q21;q23)] translocation is present in 80% of infant, 2% of children, and 5-10% of adult

The BCR-ABL1 translocation [t(9;22)(q34;q11), also known as Philadelphia chromosome] is found in 5% of pediatric and 25% of adult B cell ALL. An important consequence for this translocation is the over-expression of STAT5. STAT5 inactivation results in cell cycle arrest and apoptosis of BCR-ABLpos malignant B cells and BCR–ABL1pos STAT5 knockout mice do not develop leukemia (Malin et al., 2010). Interestingly, genome-wide analysis of B cell ALL has identified mutations in the STAT5 upstream regulators JAK1 and JAK2 in up to 10% of patients, and patients BCR-ABLpos or with JAK1&2 mutations have a similar gene expression profile and prognosis (Malin et al., 2010). JAK2 mutations lead over-expression of CRLF2 (also known as thymic stromal lymphopoietin receptor) which forms a heterodimeric complex with the IL-7R (Harvey et al., 2010). In a subset of cases, CRLF2 promotes constitutive dimerization and cytokine-independent proliferation. Finally, high expression levels of the short Ikaros isoforms, particularly the dominant negative Ik-6, are also associated with high risk leukemia (Sun et al., 1999). Most of the BCR-ABLpos B ALL patients have deletions in IKZF1 and increased levels of the short isoforms; however, Ik-6 has also been found to be elevated in BCR-ABLneg patients (Mullighan et al., 2008). It has been proposed that the high level of Ikaros short isoform expression is due to genetic lesions. Supporting this idea, IKZF1 somatic deletions have been found in a number of recurrences and are strongly associated with minimal residual disease (Mullighan et al., 2009). A summary of homeostatic and leukemic

expression of transcription factors along the B cell pathway is shown in Figure 5.

possibility of microenvironmental cues leading to disease.

**4.3 Leukemic microenvironmental cues?** 

Despite these important advances in the definition of genetic abnormalities that are prevalent in ALL, the disease is heterogeneous at the molecular level, and possibly it is the result of combination of genetic and epigenetic alterations. Furthermore, high frequencies of ALL cases seem not to be associated to intrinsic genetic abnormalities, opening the

The complexity of leukemogenesis increases when we consider the indubitable influence of the bone marrow microenvironment in the hematopoietic development, which is a network of

particularly frequent (25%) in relapsed children (Harvey et al., 2010).

undetermined (van der Weyden et al., 2011).

ALL (McCarthy, 2010).

Much has been learned about identity, function and intercommunication of seminal cells within the hematopoietic system from animal models. However, our understanding of the hierarchy and regulation of human stem/progenitor cells is still incomplete and the hematopoietic charts have been in constant re-construction over the last few years. Furthermore, while it has long been recognized that intrinsic abnormalities in primitive hematopoietic cells may cause hematological disorders, it has also become clear that changes in both cell composition and function of the bone marrow microenvironment might govern stem cell activity and lead to disease. Future progress in these areas will be decisive to suggest novel classification, prognosis and treatment venues.
