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Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09 Page 147

Table 2. Recurrent XPO1 mutations in hematological malignancies. More than 90% of the reported mutations are missense
changes affecting XPO1 “hotspot” residue E571
Type of malignancy Samples with XPO1 mutations Ref.
Chronic lymphocytic leukemia 4/165 (2.4%) [105]
2/105 (1.9%) [106]
6/192 (3.1%) [107]
7/160 (4.4%) [108]
33/969 (3.4%) [109]
1/10 (10%) [110]
6/24 (25%) [111]
4/159 (2.5%) [112]
2/12 (16.7%) [113]
13/136 (9.5%) [114]
25/538 (4.6%) [115]
17/114 (14.9%) [116]
2/25 (8%) [117]
14/180 (7.8%) [118]
7/61 (11.5%) [119]
38/486 (7,8%) [120]
25/436 (5.7%) [101]
4/56 (7.1%) [121]
28/288 (9.7%) [122]
Aggregate chronic lymphocytic leukemia 238/4116 (5.8%)
Primary mediastinal B-cell lymphoma 28/117 (24%) [100]
7/18 (38.9%) [123]
Aggregate primary mediastinal B-cell lymphoma 35/135 (25.9%)
Hodgkin’s lymphoma 22/91 (24.2%) [104]
5/19 (26%) [100]
6/34 (18%) [124]
Aggregate Hodgkin’s lymphoma 33/144 (22.9%)
Other diffuse large B-cell lymphoma 1%-3% [123]
0%-1.5% [100]

In addition, XPO1 transcription has been reported to be regulated by cMyc and p53 [102,103] , two proteins
that are frequently altered in cancer. Conceivably, disruption of this regulation may contribute to aberrant
XPO1 expression in some tumors, although further studies are required to test this possibility.

A recurrent XPO1 gene mutation in hematological malignancies
Missense mutations of the glutamic residue E571 (mostly E571K) have been detected in around 25% of
patients with two specific types of hematological malignancies: primary mediastinal B-cell lymphoma
(PMBL) [100] , and classical Hodgkin’s lymphoma (HL) [104] . The E571 “hotspot” mutations in XPO1 were
[105]
first detected by whole genome sequencing analysis of CLL samples . A large number of targeted stud-
ies [100,101,104-124] [Table 2] have subsequently confirmed the presence of E571 missense mutations in around 5%
of CLL patients.

In CLL, the presence of XPO1 mutations is often associated with unmutated IGHV status [105,109,120] , but does
[120]
not seem to be a marker of poor patient prognosis . Similarly, HL patients with XPO1 mutations do not
[104]
appear to have a worse prognosis than patients with wild type XPO1 . In contrast, a shorter progression-
free survival was reported for PMBL patients bearing XPO1 mutations [100] . Interestingly, it has been sug-
gested that XPO1 mutations could represent useful biomarkers to evaluate minimal residual disease in HL
[125]
and PMBL .
[126]
[127]
Isolated instances of mutant XPO1 have been reported in esophageal and thyroid cancer , but XPO1
genetic alterations seem to be a very rare event in solid tumors.