**3. Functions of the miRNAs in lymphopoiesis**

Lymphopoiesis is a process by which the hematopoietic stem cells (HSCs) differentiate into lymphoid progenitors and finally into B- or T-lymphocytes [18]. In the process of differentiation, the miRNAs play an important role. miR-29a and miR-196b are highly expressed by HSCs, and their downregulation is associated with differentiation into lymphoid progenitors [19, 20]. It has been reported that miR-17, miR-24, miR-155, miR-128, and miR-181 act to prevent the differentiation of early-stage progenitors [21].

miRNA-150 is expressed in both mature B- and T-cells. The lymphoid progenitors express the miRNA-150 to give rise to the mature B-cells and assist in the transition from progenitor B-cell (pro-B) to the precursor B-cell (pre-B) stage [18]. And premature expression of miRNA-150 results in blocked transition from the pro-B-cell stage to the pre-B-cell stage [22, 23].

B-cell differentiation is regulated by the miR-155, and it has been observed that miR-155 levels are upregulated rapidly in both activated mature T- and B-cells [24]. Also, miRNA-155 regulates the differentiation of T-cells into Th type 1 cells [24, 25].

miR-181 is specifically expressed in hematopoietic cell, and its expression is dynamically regulated during early hematopoiesis and lineage commitment. miR-181 expression is high in the early B-cell differentiation stage and progressively decreases subsequently, and its ectopic expression in hematopoietic stem/progenitor cells led to an increased fraction of B-lineage cells in both tissue culture differentiation assays and adult mice [26]. Additionally, miR-181 also plays an important role in T-cell development [27].

The miRNA-15 family is an element required to promote the switch from pre-B-cell proliferation to a more differentiated stage. [28]. So, pre-B-cells lacking miRNA-15 family functions exhibit prolonged proliferation because of aberrant expression of the target genes cyclin E1 and D3, and they additionally fail to trigger the transcriptional reprogramming normal to their differentiation, resulting in a developmental block at the pre-B-cell stage [28].

Six miRNAs, miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1 are part of the miR-17-92 cluster; these small molecules are important for mature B-cell development. Absence of the cluster leads to the development of disorders in the maturation from pro-B to pre-B stage [29]. Ventura et al. using miR-17-92-deficient mice found that B-cell development is inhibited at the pro-B to pre-B stage differentiation [30]. The above shows that if the miR-17-92 family miRNAs control the pro- to pre-B transition during B-cell development [31]. Likewise, it has been showed that in helper T cells, the miR-17–92a cluster is critical for the differentiation from Th1 cells [32].

miR-29b is increased in Th1 cells, and the levels from this miRNA decrease significantly upon T cell activation. So, the miR-29 expression can serve as a regulator

*Advances in Hematologic Malignancies*

aberrant expression of different miRNAs in cancer [6].

may be a potential therapeutic target.

**2. MiRNA biogenesis**

Leukemia is a clonal disorder in which the normal hematopoiesis is replaced by a malignant clonal expansion of immature hematopoietic cells (blasts) in the bone marrow or peripheral blood [4]. The first approach between miRNAs and leukemia was carried out by Calin et al. [5]. The author showed that the 13q14 deletion in B-cell chronic lymphocytic leukemias (B-CLLs) causes the loss of the precursor gene of miR-16-1 and miR-15a; therefore, the loss of these miRNAs is observed in approximately 70% of the CLLs [5]. Interestingly, it has been reported that at fragile sites, minimal regions of amplification (minimal amplicons), or common breakpoint regions fragile sites, minimal regions of loss of heterozygosity, and genomic regions related with cancer code for approximately 50% of the miRNAs, hence the

The participation of miRNAs in different biological and cellular processes under pathological and normal conditions makes them good candidates in the investigation of functional markers for differential diagnosis, prognosis, and development of new therapeutic regimens, through the investigation of their molecular targets. In this chapter, the role of miRNAs expression profiles in ALL that could be used for classification of the disease establishing specific diagnoses and prognostic values is summarized. Likewise, the relation between the miRNA dysregulation and ALL

The miRNA genes are transcribed by RNA polymerase II (Pol II) in the nucleus, and the primary miRNAs transcripts (pri-miRNAs) contain cap structures as well as poly(A) tails [7, 8]. The pri-miRNA transcript is processed by the microprocessor complex (Drosha/DGCR8), which crops the pri-miRNAs, producing a pre-miRNA

**58**

**Figure 1.** *miRNA biogenesis.* of Th1 differentiation [33]. Expression of miR-21 promotes Th2 differentiation in nonpolarized T cells [34]. miR-126 is another miRNA that also regulates the differentiation of the Th2 cells [35].
