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A. Frisch and Y. Ofran
Driver mutations and aberrations in Philadelphia chromosome-like acute lymphoblastic leukemia
In their landmark analysis of 1,725 ALL patients, Roberts et al. found kinase-activating mutations in more than 90% of patients with Ph-like expression.4 The large variability of genetic alterations recognized in patients with Ph-like ALL makes further sub-categorization a chal- lenge. For the purpose of a clinically oriented discussion, we believe clustering Ph-like ALL into the following four subgroups would be helpful.
CRLF2-associated Philadelphia chromosome-like acute lymphoblastic leukemia
The CRLF2 protein is a cytokine receptor which het- erodimerizes with interleukin-7 receptor (IL7R)-α, and upon binding to its ligand (thymic stromal lymphopoi- etin) activates the JAK-STAT pathway. This activation leads to cell proliferation without concomitant differenti- ation.5 In ALL, high expression of CRLF2 has been shown to correlate with reduced survival.4,6,7 Several genotypes are associated with high CRLF2 expression, including a chromosomal translocation with IGH-CRLF2 fusion, a cryptic interstitial deletion which results in a P2RY8- CRLF2 fusion and CRLF2 point mutations engendering uncontrolled receptor activation.
The IGH-CRLF2 translocation is an early event in leukemogenesis and remains stable in relapse, while the P2RY8-CRLF2 translocation takes place later during dis- ease development, is often subclonal and cannot be rec- ognized in one-third to one-half of relapsed patients.8,9 Additionally, CRLF2 expression is 10-100-fold higher in patients with IGH-CRLF2 than in those with the P2RY8- CRLF2.5,10,11 With regard to the prognostic impact, the relapse risk of IGH-CRLF2 ALL patients has been shown to be twice as high as that of P2RY8-CRLF2 ALL patients.12
Deregulation of CRLF2 expression is likely to require
additional players to drive the leukemic process. In an
ALL cell line with the IGH-CRLF2 translocation, knock-
down of CRLF2 was not found to reduce proliferation of
leukemic cells dramatically.5 About half of ALL patients
with deregulated CRLF2 also have mutations in the JAK-
STAT pathway4,7 and these latter are associated with a
worse prognosis.4,13 In an analysis by the German
Multicenter Study Group for Adult ALL (GMALL), one-
third of adult patients with high CRLF2 expression were
not found to harbor translocations or point mutations
involving CRLF2.14 Similarly, in a recently published
study, the CRLF2 translocation was identified in only
80% of Ph-like ALL patients demonstrating high CRLF2
expression.15 In fact, high CRLF2 immunophenotypic
expression does not per se confer a worse prognosis, if it
is not accompanied by CRLF2 genetic aberrations.11
Notably, high CRLF2 expression is reported to be signifi-
cantly more frequent among patients of Hispanic ethnici- ty.12,16
Mutations/deletions in the IKZF1 gene are prevalent in patients with Ph-like ALL1,17,18 and the presence of these mutations may be a better predictor of a poor prognosis than a high level of CRLF2 expression per se.17 Interestingly, a Chinese group recently demonstrated that IKZF1 is an epigenetic regulator of CRLF2, and IKZF1 mutations/deletions can lead to overexpression of CRLF2.19
ABL-class translocations
Translocations involving the pro-oncogenes ABL1,
ABL2, CSF1A and PGDFRB are evident in about 15% of Ph-like ALL cases.4,20 Due to the translocations, these genes lose their normal regulatory control; however, no specific partner genes, among the many reported, have been iden- tified as being of particular prognostic significance. The presence of any of these translocations is considered suffi- cient for the diagnosis of Ph-like ALL.20 The translocations in question are mutually exclusive with CRLF2 and JAK- STAT mutations but, as in other Ph-like subgroups, are often concomitantly present with IKZF1 mutations/dele- tions.4,20 Patients with ABL-activating translocations usual- ly respond poorly to therapy, continue to have measurable residual disease (MRD) after induction20 and should be treated with ABL inhibitors, as discussed later.
EPOR and JAK2 translocations
EPOR translocations, capable of partnering with multi-
ple different genes, are grouped together with JAK2 translocations as they share the same mechanism of inducing cell proliferation through constitutive activation of the JAK pathway. These translocations are easy to rec- ognize by fluorescence in situ hybridization (FISH) analysis and they are associated with a poor prognosis.4,21,22 EPOR- involving translocations lead to truncation of the erythro- poietin receptor (EPO-R), its stabilization and overexpres- sion, resulting in downstream activation of the JAK2 path- way.23 These chromosomal aberrations comprise about 10% of Ph-like ALL alterations, are associated with IKZF1 mutations or deletions and could potentially be targeted with JAK inhibition.17
JAK/STAT or RAS mutations:
This subgroup accounts for about 15-20% of Ph-like
ALL cases. It includes genetic alterations of IL7R, FLT3, SH2B3, JAK1, JAK3, IL2RB and RAS genes.24 These muta- tions are all subclonal4 and there is paucity of data regard- ing the dynamics of their alterations in relapse. Remarkably, IKZF1 is less common in this subtype of Ph- like ALL than in the above-mentioned ones.4,20,22 The prog- nosis of these patients is believed to be better than that of patients with other subtypes of Ph-like ALL.4,22 Individuals presenting with a RAS mutation as their sole driver muta- tion share both biological and clinical characteristics with the above-delineated JAK/STAT-derived group. Biologically, JAK/STAT and RAS signaling pathways are closely connected. Notably, other kinase mutations, i.e., NRAS, KRAS, PTPN11, and NF14 are observed not only in Ph-like ALL but also in hyperploid ALL.25,26 They are also found, with different prevalences, in all other subgroups of Ph-like ALL.4,20,22
Clinical presentation and diagnostic approaches to Philadelphia chromosome-like acute lymphoblastic leukemia
The prevalence of Ph-like ALL in cohorts of newly diag- nosed pediatric patients is about 10-20%,1,3,4,18 and rises to 20-30% in adults.13,14,27 Ph-like cases are by definition BCR/ABL-negative, and are also always MLL-, ETV/RUNX1- and TCF3/PBX1-negative. Thus, they con- stitute a subgroup within the B cell other ALL.17,28 It has been previously reported that some patients may present
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