Cytokine Receptor-like Factor 2 (CRLF2) Overexpression in Myeloid Malignancies Secondary to Multiple Isodicentric Y Chromosomes: A Novel Cytogenetic Entity?

Background:

Cytokine receptor-like factor 2 (CRLF2) overexpression is well-defined in B-cell and Ph-like ALL (~50%) with the CRLF2/IGH (76%) and P2RY8/CRLF2 (17%) rearrangements being the most common. CRLF2 is located on the pseudoautosomal region or PAR1 of both the short arm of X (Xp22.3) and Y (Yp11.3) chromosomes and its over-expression has not been previously described in myeloid neoplasms. Multiple isodicentric Y chromosomes, which have two centromeres and two copies of the short-arm of the Y chromosome, have the potential to produce amplification of CRLF2, leading to overexpression. We describe three cases of myeloid neoplasia, two with a diagnosis of myelodysplastic syndrome (MDS) and one with a diagnosis of acute myeloid leukemia (AML), in which cytogenetic studies demonstrated multiple copies of an isodicentric Y chromosome. CRLF2 overexpression was anticipated and confirmed via RNA sequencing in one patient. The clinical significance of CRLF2 overexpression is profound as it is known to activate the JAK-STAT pathway and is potentially targetable using tyrosine kinase inhibitors (TKIs).

Case series:

A similar genetic pattern was identified in three older males with a known diagnosis of myeloid malignancy, two of whom had MDS and one AML. The first patient is a 57-year-old man with a diagnosis of NPM-1/FLT3 ITD wt AML. Diagnostic cytogenetic abnormalities included 46-53, X, idic(Y)(q11.2)x1-8[cp12]/46,XY[8]. The second case is that of an 88-year-old man with monoclonal gammopathy of undetermined significance (MGUS), which progressed to multiple myeloma (MM) with trisomy 11. Two years after his diagnosis of MM, he was diagnosed with MDS with ringed sideroblasts (MDS-RS) with less than 5 per cent blasts, and the diagnostic karyotype result was 50-52,X,idic(Y)(q11.22)x3-4,+12. He had been treated with lenalidomide, dexamethasone and bortezomib. The third case is that of a 71-year-old man with transfusion-dependent anemia diagnosed as MDS-EB-1, with cytogenetic abnormalities at diagnosis being 50-54,XY,+idic(Y)(q11.2)x2-4,+8,+21[cp10]/46,XY[10]. Next generation sequencing identified pathogenic mutations in ASXL1 (c.1900_1922del; p.Glu635Argfs*15, 14%), IDH2 (c.419G>A; p.Arg140Gln, 37%) and SRSF2 (c.284_307del; p.Pro95_Arg102del, 36%). A bone marrow sample from this patient was subjected to RNA sequencing, and demonstrated overexpression of CRLF2, but not of SRY; confirming our hypothesis of multiple dicentric Y chromosomes resulting in CRLF2 overexpression (Figure 1).

Discussion and Conclusions:

Activation of JAK-STAT signaling is seen in Philadelphia chromosome positive (Ph) B- lymphoblastic lymphoma/leukemia (B-ALL) or Ph- like B- ALL and is therapeutically targetable with TKIs. Further, rearrangement of CRLF2 is not only associated with mutation of JAK kinases but also alteration of IKZF1, hispanic/latino ethnicity and a poor outcomes in pediatric B- ALL. Although the IGH-CRLF2 and P2RY8-CRLF2 rearrangements have been seen in up to 76 and 17 per cent of cases of adult Ph-like B-ALL cases respectively, there exist no reports of CRLF2 expression abnormalities in myeloid neoplasms (Jain N et al. Blood 2017).

With the help of our series we document that: 1. Multiple isodicentric Y chromosomes are a unique cytogenetic abnormality that merits recognition and further clinical characterization in myeloid neoplasia. 2. The presence of up to eight isodicentric Y chromosomes, with up to 16 copies of the Y short arm, suggests the possibility of CRLF2 overexpression. 3. RNA sequencing can help confirm these results; thus providing relapsed/refractory patients with potential targeted salvage therapies.

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