T lymphocytes like all blood cells are progenies of a single multipotent hematopoietic stem cell (HSC). The existence of HSCs was proven by Till and McCulloch in 1961 when bone marrow cells injected into irradiated mice formed multilineage colonies in their spleens. These cells were called colony forming units (CFU-S) and they have potential for self-renewal and differentiation into all types of blood cells(Till and McCulloch 1961, Wu et al. 1968). For lymphocyte development HSCs migrate from the bone marrow, differentiate in the thymus into immunocompetent cells and seed the peripheral lymphatic organs. This process occurs during fetal development (for review see (Godin and Cumano 2002), but also during the adult life of an individual since T lymphocytes have to be continuously replenished. Transplantation experiments proved that thirty hematopoietic stem cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood cell types in vivo (Spangrude et al. 1988). Because it is extremely important to produce immunocompetent T cells the process of their maturation and development is strictly regulated and is succumb to very strict check points at several stages of differentiation. In this context we’ll discuss Ikaros family transcription factors as major regulators of T lymphocyte development.
2. Committed lymphocyte precursor
For a long time it has been postulated analogously to committed myeloid precursors that there is a committed lymphocyte precursor. However the first experiments that showed the existence of a committed lymphocyte precursor was described in the early 90tis when a new population of cells in the thymus was found and its features described (Wu 1991, Wu et al. 1991). These cells expressed most markers of the multipotent hematopoietic stem cells like Thy-1lowCD44+H2k+Sca-1+ but they expressed Sca-2 and low levels of CD4. These cells were negative for all mature blood cells markers lymphocytes (CD8-CD3-Ig-), macrophages (Mac-1-), granulocytes (Gr-1-) and erhytrocytes (TER119-), lineage negative, (Lin- cells). Their Ig and TCR receptor genes were in germline configuration. The described precursors represent 0.05% of the cells in an adult mouse thymus. If the cells were sorted and transferred by intrathymic injections (
From the clinical point of view defining the earliest lymphoid precursor is important for a rapid engraftment and protection from infections after hematopoietic stem cell transplantation in chemotherapy or irradiation compromised patients (Arber et al. 2003, Holländer et al. 2010).
3. Ikaros transcription factors
Mechanisms and factors that regulate lymphocyte development from stem cells have to be very accurate since any alteration of this process may lead to serious diseases like leukemia.
Transcription factors from the Ikaros family play an essential role in the commitment of hematopoietic progenitors into the lymphoid lineage as well as in the choice of effector functions at later stages of development(Georgopoulos 1994, Sun et al. 1996, Wang et al. 1998, Cortes et al. 1999). Their role has been addressed by gene targeting and such gene inactivation studies have identified Ikaros, Aiolos and Helios as transcription factors required for the maturation of lymphocytes(Morgan 1997, Hahm 1998, Kelley 1998). It has been shown that mice homozygous for a deletion in these genes undergo remarkable changes in their lymphocyte populations and also those ageing animals with the same mutation develop lymphoproliferative disorders. A number of studies show that Ikaros genes in both mice and human malignancies might be deregulated (Winandy et al. 1995, Nichogiannopoulou et al. 1999, Nakase et al. 2000, Nakayama et al. 2000, Nakase et al. 2002, Rebollo and Schmitt 2003, Dovat et al. 2005; Mullighan et al. 2008, Matulic et al. 2009, Billot et al. 2010). Therefore we addressed the question whether a combination of transcription factor failures may contribute to the development of human lymphoma. We amplified human mRNA from formalin fixed paraffin embedded tissues from lymphoma patients in order to have consistent and well defined groups of patients. Hence, we were able to analyze Ikaros, Aiolos and Helios mRNA from archive tissue specimens from patients with Hodgkin’s and non- Hodgkin’s lymphoma and follicular hyperplasia (Antica et al. 2008, Antica et al. 2010). Further we and others show a deregulation in human leukemia. Acute lymphoblastic leukemia (ALL) is characterized by the Philadelphia chromosome (Ph) which encodes the BCR-ABL1 tyrosine kinase, the most frequent cytogenetic abnormality (∼25–30% of cases)(Mancini et al. 2005). Deletion of the IKAROS gene (
In the last ten years a new system, besides fetal thymic organ cultures (FTOC) or reaggregation cultures, for T cell growth
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