• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • In addition to grouping cases of B


    In addition to grouping cases of B-ALL by cell of origin, these lymphomas can also be subcharacterized by genetic rearrangements. Fusion of the purinergic receptor P2RY8 promoter to the CRLF2 (cytokine receptor like factor 2) gene frequently occurs in B-ALL but reports of the functional consequences of this rearrangement have been conflicting. Although P2RY8-CRLF2 fusions were significantly correlated with poor outcome in adolescent and adult patients [15], [16], the consequences of the fusion in pediatric B-ALL is less clear as some studies have found it to be associated with poor outcome [17], [18], [19] whereas others have not found any significant correlation [20], [21]. A meta-analysis of these studies concluded that presence of the P2RY8-CRLF2 fusion was in fact significantly associated with poor prognosis of relapse-free survival and event-free survival [22]. Another finding among these studies was that P2RY8-CRLF2 was more common in B-ALL patients with trisomy 21 [19], [23], [24], [25], [26] or intrachromosomal amplification of chromosome 21 [27] than those with normal chromosome 21 [1], [18], [19], [20], [21], [25], [26], [28], [29], [30]. P2RY8-CRLF2 rearrangements were significantly enriched in patients harboring Rivaroxaban sale of the lymphoid lineage-directing transcription factor IKZF1 in one study [31] but not correlated in another study, and this discrepancy is suggested to be correlated to ethnicity [1]. Interestingly, reduced protein expression of IKZF1 has also been associated with upregulation of the orphan GPCR GPR132 (also known as G2A) in B-ALL patients that do not harbor the BCR-ABL fusion, which encodes a tyrosine kinase oncoprotein [32]. In fact, mice transplanted with BCR-ABL transduced bone marrow deficient of GPR132 developed tumors more quickly and had accelerated tumor progression and death compared to those with wild type GPR132 suggesting that GPR132 acts as a negative regulator of BCR-ABL induced leukemogenesis [33]. Other GPCRs that have been described in B-ALL include oncogenic roles for the prostaglandin receptor PTGER2 [34], [35], [36], [37] and orphan receptor GPR34 [38], increased protein expression of the thrombin receptor F2R (also known as PAR1) at significantly higher levels than lymphocytes from healthy donors [39] and decreased expression of S1PR1 and S1PR2 transcripts [40] and the tachykinin receptor TACR1 in tumor compared to normal B lymphocytes [41]. A summary of all GPCRs reported in B-ALL is shown in Table 2.
    Chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that arises from CD5+ B cells. CLL is the most frequently occurring leukemia in Western countries and has an extremely variable prognosis that can range from stable, indolent disease not requiring intervention to aggressive malignancy [42]. CLL is often characterized by immunoglobulin heavy-chain variable region gene (IGHV) mutation status. Unmutated IGHV CLL originates from pre-germinal center cells and is defined as having less than a 2% difference between leukemic clone and germline DNA sequence in the IGHV region. Mutated IGHV arises from post-germinal center cells and contains a 2% or greater difference between leukemic clone and germline IGHV sequence and has a significantly better prognosis than unmutated IGHV [43]. CLL that localizes to lymph nodes is also known as small lymphocytic lymphoma (SLL) and represents a subset of CLL. A variety of receptors spanning multiple GPCR families have been studied in CLL and recent attempts to target members of the lipid receptors in vitro and in vivo have shown a range of success. The sphingosine-1-phosphate (S1P) receptors S1PR1 and S1PR2 transcripts were found to be downregulated in CLL compared to control B cells [40], with S1PR1 expression particularly reduced in unmutated IGHV CLL patients and S1PR2 impaired in both mutated and unmutated CLL [43]. This downregulation is thought to be due to cell interaction with the tumor microenvironment to regulate egress of malignant cells from the lymphoid tissues to peripheral blood [44]. Treatment with Syk, Btk, and B cell receptor (BCR) inhibitors has been effective at increasing S1PR1 protein expression to induce CLL cell mobilization into the blood so that cells are more sensitive to cytotoxic drugs [44], [45], [46].