A wide spectrum of genetic alterations (>60), including translocations, cryptic rearrangements, sequence mutations and copy number changes have been described in Ph-like ALL, with slight differences in prevalence across age. These alterations drive constitutively active kinase or cytokine receptor signaling, many of which have been shown to be druggable with a variety of kinase inhibitors. The most commonly mutated pathways are the ABL and JAK-STAT pathways with multiple rearrangements and lesions that converge on downstream ABL/JAK-STAT signaling. Founder alterations may be grouped into three types: (i) JAK/STAT alterations including mutations activating cytokine receptors (e.g., CRLF2 and IL7R); gene fusions hijacking cytokine receptor expression (e.g.,
IGH-CRLF2
and
P2RY8–CRLF2
); gene fusions and/or mutations activating kinases (e.g.,
JAK1
,
JAK2
,
JAK3
,
TYK2
); and rearrangements hijacking and truncating cytokine receptor expression (e.g., cryptic
EPOR
rearrangements); (ii) fusions involving ABL-class genes (
ABL1
,
ABL2
,
CSF1R
,
LYN
,
PDGFRA
,
PDGFRB
); (iii) less common fusions (
FLT3
,
FGFR1
,
NTRK3
,
PTK2B
) whose number is growing with increasing sequencing studies of different cohorts.
- acute lymphoblastic leukemia (ALL)
- Ph-like ALL
1. JAK/STAT Alterations
Approximately 50% of patients with Ph-like ALL harbor rearrangements of the cytokine receptor- like factor 2 (
) gene, located on the pseudoautosomal region 1 (
) of chromosomes Xp22 and Yp11 [1][2][3][4]. In normal conditions CRLF2 dimerizes with the α- subunit of interleukin- 7 receptor (IL7RA) to form a heterodimeric thymic stromal lymphopoietin receptor (TSLPR) which actives downstream JAK2/STAT5 and thePI3K/AKT/mTOR pathways [5][6][7] and is implicated in early B-cell development [8].
deregulation results from three main mechanisms: (1) a cryptic rearrangement that juxtaposes
to the immunoglobulin heavy chain locus (
); (2) a focal deletion in the pseudoautosomal region of the sex chromosomes resulting in P2Y receptor family member 8 (
)-
fusion that positions
under the control of the
promoter; (3) and less frequently by an activating
point mutation, F232C [9][10][11][12][13][14][15][16][17]. Rearrangements of
account for 24% of pediatric patients with NCI SR Ph-like ALL [18], 55% of children with HR disease [19] and 50% to 60% of adolescent and adult patients with Ph-like ALL cases [1][20][2][9][10][21].
fusions occur more commonly in younger children and in patients with Down syndrome (DS) ALL [11][13], while
fusions are detected more frequently in older patients and patients of Hispanic ethnicity [22]. In a genome-wide association study of
-rearranged ALL, the inherited
variant rs3824662 was associated with
rearrangement,
mutation,
deletion, variation in
expression and increased risk of relapse [23]. This variant is markedly more common in patients of Hispanic ethnicity (~40%) or Native American (~50%) genetic ancestry, while is it detected in only 14% of Europeans [23][24]. The point mutation changing phenylalanine 232 to cysteine in CRLF2 has been identified in 9% of DS-ALL patients [13] and 21% of adult B-ALL patients [12]. In in vitro assays, the expression of CRLF2 F232C in the absence of co-expression of mutant JAK2 promotes JAK2 signaling activation and cell transformation [12][13][25].
rearrangement and overexpression is associated with worse outcome compared to cases with lack of
alterations [3][22][26][27]. However, the poor prognostic impact of
overexpression is overcome by
–like signature and
deletion in the Dutch Childhood Oncology Group trials and German Cooperative ALL trials [25]. In about half of
-rearranged pediatric Ph-like ALL cases, concomitant
and
(most commonly in the pseudokinase domain at R683) mutations occur. In adults, the frequency of
mutations in patients with
rearrangement is lower, with a ratio of 1:4 with
the most common mutation is represented by V658F which is the homolog of JAK2 V617F, hotspot in myeloproliferative neoplasms. Other alterations leading to JAK/STAT activation target
,
,
, and
genes. Collectively these alterations are approximately two-fold higher in children (14%) compared to adolescents (5.0%), and adults (7.3%) [1][2][3].
mutations occur in exon 6 and are mainly in-frame insertion/deletions in the juxtamembrane-transmembrane domain or, rarely, a serine-to-cysteine substitution at amino acid 185 in the extracellular domain [26]. Independent of
rearrangements, JAK-STAT signaling activation can result from
(~7%) or erythropoietin receptor (
5%) -rearrangements.
Over 20 different
gene fusion partners have been reported (most commonly
,
,
, and
), making
the most promiscuous gene in Ph-like ALL. All fusions preserve the JAK2 kinase domain and result in STAT5 activation and growth factor independence, making cells expressing these fusions amenable to JAK2 inhibitors.
Common
rearrangements involve juxtaposition or less frequently translocation of the
gene in proximity of a strong enhancer, such as that of the immunoglobulin heavy (
) or kappa (
) loci, that drives its expression. Less frequent rearrangements involve insertion of
into the upstream region of
or the
loci [1][27]. All these rearrangements clip off the C-terminal cytoplasmic tail, thus preserving the proximal tyrosine requested for activation and removing almost all tyrosine sites required for shutting off the receptor signaling and down-regulate and internalize the receptor. This leads to transformation in in vivo models and sensitivity to a variety of different JAK2 inhibitors in in vitro and in vivo models. While
fusion due the translocation t(14;19)(q32;p13) can be detected by fluorescence in situ hybridization (FISH) [28], the other
rearrangements are cryptic and challenging to detect without using next-generation sequencing (NGS) technologies. The prevalence of
rearrangements has a peak in young adults (9%) compared to children and adolescents (5% and 3%, respectively). They are rarely detected in adults (1%) [9][27].
and
rearrangements are associated with the poorest outcome compared with the other molecular Ph-like subtypes [2][9].
2. Fusions Involving ABL-Class Genes
The ABL-class gene fusions include rearrangements of ABL proto-oncogene 1 (
e.g., to
), ABL proto-oncogene 2 (
e.g., to
), colony-stimulating factor 1 receptor (
e.g., to
,
), platelet-derived growth factor receptor beta (
e.g., to
) and
[29]), with multiple partner genes, with
and
being the most common. The prevalence of these rearrangements is 17% in children, 9% in adolescents, 10% young adults and 9% older adults [1][2][30][3]. Patients with ABL-class fusions respond poorly to chemotherapy regimens, and the
fusion in particular is associated with induction failure [31][32][33]. All fusions preserve the tyrosine kinase of the ABL-class gene and promote constitutive kinase signaling that confers the ability to survive and grow independently of cytokine in vitro [34]. Imatinib, the dual ABL1/SRC inhibitor dasatinib or other TKIs inhibit the downstream signaling induced by each of these chimeric fusion proteins [1][35][36] and are currently used in clinical trials. The best and first example is provided by the inhibition of
fusion by imatinib [33][35][36][37][38]. The emergence of kinase domain point mutations may represent a potential mechanism of relapse in
or other kinase driven-subtypes in Ph-like ALL. Recently, the T681I gatekeeper mutation has been demonstrated to be the most common resistant mutation in
Ph-like ALL to both imatinib and dasatinib in in vitro screens and it was associated with a trend towards increased risk of relapse in patients harboring T681I subclones at diagnosis compared to T681I-negative patients [39].
3. Other Kinase Fusions and Genetic Aberrations
Around 5% of Ph-like ALL cases harbor gene fusions or mutations involving
and
. Among those, one percent of cases harbor the fusion between
and
encoding a member of the tropomyosin receptor tyrosine kinase (TRK) family [40]. This fusion is not unique of Ph-like ALL since it has been identified in a range of hematological malignancies, such as acute myeloid leukemia [41], infantile sarcoma [42][43] and solid tumors [44][45][46][47]. In preclinical models, ETV6-NTRK3 has been shown to promote the development of an aggressive B-ALL and to be exquisitely sensitive to the TRK inhibitors larotrectinib (LOXO-101) or PLX7486 (Plexxikon) in both patient derived xenograft models and in B-ALL patients with
[44][48][49]. Recently, a clinical response to larotrectinib has been reported in an adult Ph-like ALL with cryptic
rearrangement and NRASGly12Asp mutation. The patient failed to respond to multiagent chemotherapy and relapse after investigational CD19-directed chimeric antigen receptor T-cell therapy with a clone positive for
but not anymore for the NRASGly12Asp mutation. The relapsed leukemia progressed with further chemo- and immunotherapy but showed substantial leukemic cytoreduction using the TRK inhibitor larotrectinib [50]. Fusions of the B Cell Linker Protein (
) or
gene to
(also known as
) have been also described [9][51].
encodes a cytoplasmic adapter protein important for B-cell development and function by activating BCR downstream signaling [52], while
encodes a encodes a template-independent DNA polymerase that catalyzes the addition of deoxynucleotides and that is highly expressed in normal and malignant pre-B and pre-T lymphocytes during early differentiation [53].
In addition to gene fusions, RAS pathway activating mutations or deletions (
) and copy number aberrations in genes involved in B-cell development (
and
) and cell cycle regulators (
,
,
, and
) are recurrent. Deletions in
occur in around 27% of pediatric cases and in approximately 70% of high-risk pediatric patients with ALL [1]. As in
deletions confer a poor prognostic outcome [55].
deletions are significantly more common in patients carrying kinase or cytokine receptor rearrangement (
) than a sequence mutation [1][9], especially in Hispanic/Latino (H/L) children with B-ALL (29% in H/L compared to 15% of non-Hispanic Whites) where both
translocation and
deletion provide a strong biological rationale for the higher death-rate H/L experience due to B-ALL [49].
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