Common integration site.
Abstract
Stat5, c-myc, Hipk2, Fiz1, and ZFP521 to lymphomagenesis precursor B-cell lymphoblastic lymphoma/leukemia have been previously identified as a putative gene involved in the induction of B-cell lymphomagenesis. In this review, we summarize the role of ZFP521 in B-cell lymphomagenesis. Zinc finger protein 521 (Zfp521) is a novel identified gene that is responsible for pre–B-lymphoblastic lymphomagenesis through activation of pre–B-cell receptor (pre-BCR)-signaling by upregulation of adaptor genes and related kinases in the signaling downstream. The pre-BCR-signaling molecules, FLT3, CD43, and IL-7 receptor (IL-7R) were positively regulated by these genes. Stimulation of pre-BCR and/or IL-7R signaling caused aberrant upregulation of other oncogene sets such as cyclin genes, thereby inducing the growth of pre–B cells. IL-7R/Janus kinase (JAK)/STAT signaling cascade is one of the key signaling pathways that are activated in precursor B-cell lymphoblastic lymphoma/leukemia. FLT3, CD43, and pre-BCR cascades crosstalk with JAK/STAT cascade. FLT3 and CD43 cascades have the potential to enhance JAK/STAT cascade effect on pre-B cell growth. On the other hand, pre-BCR and interleukin (IL)-7 receptor exerted competitive effects on pre–B-cell growth; thus, precursor B-cell lymphoblastic lymphomagenesis is a consequence through interaction with these cascades.
Keywords
- pre–B-cell receptor
- Stat/Jak pathway
- Zfp521
1. Introduction
1.1. Summary
B-cell lymphoblastic leukemia/lymphoma (B-LBL) is a neoplasm that exhibits immature phenotype of the B-cell lineage with on-going immunoglobulin rearrangement. Understanding the activation of signal pathways in tumor cells provides significant knowledge on tumorigenesis. Surface markers interleukin-7 receptor (IL-7R), FLT3, CD43, and phenotypic marker pre–B-cell receptor are aberrantly activated in tumor cells. IL-7R is one of the developmental stage markers and is closely associated with immunoglobulin gene rearrangement in mice. In addition, these IL-7R, FLT3, and CD43 signal pathways interact with each other. The signaling molecules, JAK3, Stat5a, Fiz1, and Hipk2, play pivotal roles in these signaling pathways. In this review, we summarize the activation networks of these pathways from the perspective of the activation of adaptor molecules and immunoglobulin rearrangement.
1.2. Introduction
B-LBL is a neoplasm of B-lymphoid precursors and it is essentially identical to acute lymphocytic leukemia as it involves the bone marrow and peripheral blood [1, 2]. These lymphomas and leukemias are composed of medium-sized blast cells with scant cytoplasm, an oval nucleus, transparent nucleus, condensed chromatin, and often multiple nucleoli. The lymphoma tissues exhibit mitotic figures and are phagocytosed by macrophages after apoptosis—this histology is called “Starry sky” and is well known in Burkitt lymphoma. Distinguishing B-precursor types from T-precursor types is impossible because they share similar cytological features. Immuno-phenotypes of pre–B LBL resemble the normal immature B-cell lineages, primarily including pre–B cells, because pre–B LBL consists of ongoing immunoglobulin gene (
2. The characterization of spontaneous pre–B-cell lymphoma in SL/Kh mice
2.1. Experimental mouse model of spontaneous lymphoma
We established an inbred strain of mouse called the spontaneous lymphoma mouse strain (SL/Kh) as a model of murine leukemia virus (MLV) integration-induced B-LBL lymphomagenesis. In the experimental model, transgenic mice carrying chimera genes, such as Emu-myc mice, MT-BCR-ABL mice, [6, 7], and TEL/AML1 mice rapidly develop pre-B LBL [8–10]. Unlike these models, the SL/Kh mouse develops spontaneously in the absence of artificially introduced gene mutation; however, Zfp521 is the gene that is spontaneously and constitutively mutated by MLV insertion after the birth [11, 12].
These mice share MLV with AKR-strain mice that are susceptible to T lymphoma [13, 14]. SL/Kh mice were found to have multiple copies of the pathogenic endogenous proviral genome that are genetically transmitted through the germ line on chr 7 [12, 15]. A type of MLV expressed from this provirus infects the hematopoietic cells and MLV genome is somatically re-integrated into the host cell genome. Subsequently, B-LBL spontaneously develops with a high frequency of 95% after 6 months of birth. These lymphoma cells are positive for lambda5 and Vpreb, which are a part of the pre-BCR. Myeloid leukemia, mature B-cell lymphoma, and T-cell lymphoma are known to occur in the inbred strain of mouse [16]. Such high occurrence of identical B-lymphoblastic lymphoma/leukemia phenotypes has not been reported in other mice. The initial growth of pre–B cells in SL/Kh was proven to be independent of the provirus integration, but dependent on the bone marrow pre-B1 (
2.2. Flow cytometry analysis of B-LBL experimental lymphomas
Flow cytometric analysis is the one of the most important methods for analyzing pre–B cells. BP1, B220, IL-7R, CD24, and CD43 are the classical phenotypic markers of pre–B cells as well as λ5 and Vpreb. These markers were available for Hardy’s classification for murine B cell lineage (Figures 2 and 3) [18, 19]. These markers are a little different from those that are used for the classification of human B-cell lineages, because B220 , BP-1, CD43, and CD24 are included.
2.3. Genetic background of pre–B lymphomagenesis
3. Upregulation of proto-oncogenes in pre–B lymphomas
Retroviral tagging, such as MLV insertion, is considered as a useful method for the identification of proto-oncogenes. RTCGD (Retrovirus and Transposon-tagged Cancer Gene Database, http://variation.osu.edu/rtcgd/) is one of the established registration systems of MLV integration, and many genes were identified as the common integration site (CIS) [16].
There many identified genes that are involved in the development of hematopoietic tumors. We summarize the signaling pathways that are associated with the target genes as described in the subsequent text.
3.1. IL-7R-signaling pathway and Stat5a
In both humans and mice, the IL-7R (also known as CD127) is expressed by early B-cell progenitors, and signaling via IL-7Rα activates signal transducer and activator of transcription 5 (STAT5) and drives pro-B-cell proliferation, while inhibiting Igκ recombination [22, 23].
Gene | Mean interval (bp) | Number of integration sites |
---|---|---|
26.2 | 92 | |
55.5 | 16 | |
6 | 8 | |
89.1 | 8 | |
101.1 | 7 | |
121.7 | 3 | |
100 | 2 |
Binding of the cytokine ligands to these receptors on the outside of the cell activates the JAK3 [25]. Subsequently, the activated kinases add a phosphate group to tyrosine residues (Y449) on the IL-7Rα chain of the receptor. STAT5 then binds to these phosphorylated tyrosines. STAT5 is subsequently phosphorylated by the JAK3. The phosphorylated STAT5 forms either homodimer. Phosphorylated STAT proteins have the potential to form a dimer that can translocate into the nucleus and upregulate transcriptional activity by binding to the gamma interferon activation site palindromic (GAS) element in the promoters of the target genes. The targets encode
A comparison of the phenotype of SL/Kh lymphomas showed that when the
3.2. Zfp521 and pre-BCR pathway
The
The pre-BCR is expressed on large pre–B cells in which
Cyclin D3 and Cyclin D2 are upregulated by overexpression of the
In humans, the fusion of the Pax5, which is essential for pre–B-cell development gene, exon 7 to ZFP521 exon 4, has been observed in pre–B-cell acute lymphocytic leukemia by genome-wide analysis of genetic alterations [39]. Dysregulation of
3.3. FLT3 signaling and LBL development via Fiz1
In the absence of FL, FLT3 remains in the inactivated monomeric form. When FLT3 binds to FL, a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L. Ligand binding promotes conformational changes in FLT3 for dimerization, phosphorylation, and association with adaptor proteins such as Fiz1. The complex formation brings the intracellular domains close to each other, promoting initial phosphorylation of the kinase domain. Activated dimeric FLT3 transduces signals to the downstream effectors. In the pathogenesis analysis, FLT3 is expressed on the cell surface of most AML and ALL cells through proliferation activation and apoptosis suppression, which are caused by the stimulation of FL [41–43].
Internal tandem duplications (ITDs) occur in exon 14 or 15 of the JM, which are located directly between the transmembrane domain (TM) and tyrosine kinase region TK1 [44]. Insertions, deletions, and point mutations are frequently found in exon 20 of another tyrosine kinase region TK2.The functional kinase region is kept, and only the JM region is elongated. ITDs probably promote ligand-independent dimerization and activation of FLT3 by changing the conformation of the expressed receptor [44, 45]. In addition, another mutation was identified within the kinase activation loop, a part of the functional core. The conformational changes associated with ITDs might change the structure of the receptor such that unique adaptor proteins such as Fiz1 can now dock.
3.4. CD43 and Hipk2 in the development of B-LBL/ALL
HIPK2 is a conserved serine/threonine nuclear kinase that interacts with homeodomain transcription factors. This protein interacts with the cytoplasmic domain of CD43, which is expressed on immature pro- to pre–B cells, Fr. A-C in Hardy classification. In this immature stage, IL-7R is highly expressed and the CD43 pathway may interact with IL-7R pathway recruiting STAT5A. Hipk2 promotes Wnt signaling by stabilizing beta-catenin [49]. Hipk2 interacts with lymphoid-enhancing factor 1, which acts as a transcriptional factor, promoting c-Myc and cyclin D1 expression [50]. CD43 is an E-selectin counter-receptor highly expressed in human pre–B-cell leukemia NALL-1 cell line [51]. In our study, CD43 cross-linking resulted in an increase in STAT5A phosphorylation, when IL-7 was supplied. CD43 signaling may enhance the IL-7R signal pathway [48, 52].
4. Signaling pathway network responsible for pre–B lymphomagenesis
Probably, multiple genes are related to the activation of IL-7R-signaling pathway. Hipk2 and Fiz 1 are candidates of interaction with IL-7R pathway as well as Stat5. Considering the activation of FLT3 pathway in AML, B-LBL may share the activation pathway with AML [10]. We propose a scheme of interactions among the IL-7-, CD43-, and FLT3-signaling pathways (Figure 8) [48]. Thus, we hypothesize that these three pathways form an interacting network and affect B-LBL development. By contrast, pre-BCR pathway is activated by Zfp521 through the upregulation of BLNK [53, 54], BANK1 [37], Btk, and other pre–BCR-related molecules. Pre-BCR pathway has been considered to contribute to pre–B-cell development rather than to proliferation. Therefore, although stimulation of pre-BCR promotes pre-B cell proliferation, Zfp521 may not directly contribute to lymphomagenesis, but contribute to the stabilization of phenotype of B-LBL. Or interaction with IL-7R and pre-BCR may promote aberrant proliferation or development. Further research is required for precise understanding of the interaction between these two pathways in B-cell development.
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