Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR/ABL1ñlike (Arber et al. 2016)

The translocation IGH/CRLF2 involves a CpG break at CRLF2 and a V(D)J break at IGH locus, and produce overexpression of the CRLF2 protein (Schmäh et al. 2017).

Reports about the IGH/CRLF2 prevalence have been obtained from selected and unselected patients, mostly from retrospective cohorts; as a consequence contrasting results have been informed. The Medical Research Council (MRC) found IGH/CRLF2 in 1% of paediatric patients (Ensor et al. 2011); in adults with Ph-like this translocation has been detected in 57.6% of cases (Roberts et al. 2017). A recent study reports in ALL children and adolescents (1-18 years-old) the higher incidence of IGH/CRLF2 in patients with median age of 14 years (Schmäh et al. 2017). Another report describes a cohort of pre B-ALL patients, ranging from 1-60 years-old, with IGH/CRLF2 in 37.2% of cases (Russell et al. 2017). In general, the prevalence of IGH/CRLF2 increases with age.

ALL with BCP immunophenotype with rearrangement involving a cytokine receptor, included in the BCR/ABL1ñlike ALL subgroup.

The IGH/CRLF2 translocation results in kinase-activating lesion that causes the constitutive activation of the Jak2/STAT5 signalling pathway. The patients that harbour IGH/CRLF2 ALL could benefit from the treatment with Ruxolitinib, which blocks Jak2/STAT5 pathway (Figure 5). This treatment could potentially improve their survival (Harrison 2013)).

IGH/CRLF2 is associated with high risk National Cancer Institute (NCI) characteristics in contrast to P2RY8/CRLF2 positive patients. IGH/CRLF2 is also present in patients with high levels of minimal residual disease (MRD) (≥ 10^-3) which are consider MRD-slow early responders, based on this the group is prone to suffer relapses (Schmäh et al. 2017; Attarbaschi et al. 2012).

t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 is a cryptic rearrangement (Figures 1 and 2). It is present in patients with extra copies of the X chromosome produced by high hyperdiploidy in 19.8% of cases. To date, only one patient who presented both a PAR1 deletion ( P2RY8/CRLF2) and IGH/CRLF2 translocation has been reported (Harvey et al. 2010). Recently, two patients with coexistence of IGH/CRLF2 and BCR/ ABL1 rearrangements have been described. One patient presented both rearrangements in different clones (Russell et al. 2017); the other case showed the translocation t(Y;14) harbouring the CRLF2 rearrangement in 90% of interphases, and presented BCR/ABL1 fusion in a subset of the CRLF2-rearranged cells (Jain et al. 2017).
IGH/CRLF2 positive cells also have a high frequency (94%) of additional deletions which may reflect chromosomal instability (Schmäh et al. 2017). The most common deletions in addition to this rearrangement are found in IKZF1 (53%), ADD3 (46%) and SLX4IP (41%). Similar to patients P2RY8/CRLF2 positive, deletions in JAK1/ JAK2 (17%) are also present (Russell et al. 2017). Although IGH/CRLF2 is part of the BCR/ABL1-like ALL subtype this rearrangement is not associated with it in all cases; however, those patients with the rearrangement in coexistence with JAK2 mutations have been found that present the expression signature of the subtype (Herold et al. 2017).
Although in Down syndrome patients the P2RY8/CRLF2 deletion is more frequent, IGH/CRLF2 rearrangement is also observed (35% vs. 20% respectively) (Russell et al. 2017).

The IGH/CRLF2 rearrangement results from a cryptic translocation t(X;14)(p22;q32) or t(Y;14)(p11;q32) involving the PAR1 region, which is located in the short arm of both sex chromosomes and the immunoglobulin heavy chain locus located in the chromosome 14 (Figure 2). Represent the 20-26% of IGH translocations in B cell precursor ALL and the principal consequence is a deregulated transcription of CRLF2 by the physical juxtaposition with the IGH transcriptional enhancers (Figure 4) (Dyer et al. 2010; Chapiro et al. 2013; Jeffries et al. 2014; Yoda et al. 2010; Tsai et al. 2010).

IGH/CRLF2 translocation can result of an aberrant D-J or V-DJ recombination that involves the cryptic recognition signal sequence (RSS) in the pseudoautosomal region (Figure 4). As a result, the IGH-J or IGH-DJ regions becomes adjacent to the CRLF2 entire reading frame and the der(14) carries the junctions between IGH segments and the centromeric region of CRLF2 (Dyer et al. 2010; Chapiro et al. 2013; Yoda et al. 2010; Tsai et al. 2010).
The breakpoints occur approximately 8 to 16 Kb upstream to the CRLF2 translation start site and, there is a 311 bp cluster from positions 1,307,403 to 1,307,713 which contains 6 out of 19 described breakpoints. Tsai et al., 2010 report that 7 of 19 CRLF2 breakpoints are at 5íor 3¥sides of CpG dinucleotide sequences. Similar to the IGH-BCL2 rearrangement, at least 18 of the 19 IGH breaks in the IGH/CRLF2 translocation are compatible with standard V(D)J recombination, the IGH junction is within 30bp 5¥of an RSS and this junctions contain non templated nucleotide additions consistent with the activity of terminal deoxynucleotide transferase (Dyer et al. 2010; Chapiro et al. 2013; Yoda et al. 2010).

There is no a chimeric transcript. Usually the rearrangement relocates the CRLF2 entire coding sequence without mutation under transcriptional control of IGH enhancer and the gene is overexpressed (Dyer et al. 2010).

The IGH/CRLF2 translocation involves the disruption of both loci, based on this FISH technique using IGH and CRLF2 break-apart probes allows the detection of the rearrangement (Figure 2). These probes mark the centromeric region of each gene of red color and the telomeric region of green color. A normal cell with intact IGH and CRLF2 shows in each cell two close red (R) and green (G) fused (F) signals (2F); in a cell with the translocation, one normal F signal is conserved and one red and one green are present as a result of the breakage (1F1R1G pattern). In abnormal metaphases the hybridization with IGH break-apart probe shows a der(14) with one centromeric red signal and one telomeric green signal moved to the derivative chromosome X or Y (Russell et al. 2009).
Harvey et al. 2010 reported the IGH/CRLF2 detection using a single fusion extra signal probe consisting of two bacterial artificial chromosomes (BAC) clones flanking CRLF2 labeled with red fluorochrome, and a third BAC clone centromeric to IGH labeled with green fluorochrome. In this assay an IGH/CRLF2 positive cell shows the 1F2R1G pattern.
Yoda et al. 2010 amplified the IGH/CRLF2 junction on der(14) by PCR using a common IGHJ primer and spaced primers 5` of the CRLF2 coding sequence.

There is not a fusion protein

The overexpression of CRLF2 due to the IGH/CRLF2 translocation results in its homodimerization at cellular membrane. This leads directly to constitutive activation of JAK2/STAT5, PI3k/ MTOR andSRC signaling pathway, causing the leukemic blast proliferation and survival (Figures 3 and 5) (Zhong et al. 2014). Nevertheless, the IGH translocation is not enough for the establishment of the neoplastic phenotype, concurrent activation of synergistic oncogenes and loss of tumor suppressor gene functions are necessary (Moorman et al. 2012). In the near future, inhibitors for the JAK2 pathway, Ruxolitinib, and for Src pathway, Dasatinib, could be used in order to counteract oncogenic effect caused by IGH/CRLF2 in ALL patients.

IGH/CRLF2