Table S9. Genes that may mediate transformation by NUP98 fusions.
Upregulated Genes
Homeobox
Several genes that encode homeodomain-containing transcription factors
genes
are upregulated by NUP98 fusions. These include the clustered (type I)
HOX genes HOXA3, HOXA5, HOXA6, HOXA7, HOXA9, HOXB3,
HOXB5, HOXB6, and HOXB7 as well as the non-clustered (type II)
homeobox genes, MEIS1 and PBX3. Homeobox genes play important
roles in normal hematopoiesis and in leukemogenesis (1, 2). Several are
expressed early in hematopoiesis and downregulated with differentiation
(3). Overexpression of HOXA9 in mouse bone marrow causes AML that
is accelerated by coexpression of MEIS1 (4). MEIS1 accelerates the
induction of AML by NUP98-HOXA9 in mice (4). Several homeobox
genes including HOXA9, HOXA7, and MEIS1 are frequently
overexpressed in human AML and are associated with worse prognosis
(5-9). Homeobox gene overexpression is believed to mediate the
leukemogenic effects of MLL fusions (10). The induction of several
homeobox genes by both NUP98-HOXA9 and NUP98-DDX10 suggests
that homeobox genes play an important role in leukemic transformation
by NUP98 fusions. This notion is supported by data showing that
homeobox genes are upregulated in murine bone marrow cells
expressing other leukemogenic NUP98 fusions such as NUP98HOXD13, NUP98-PMX1, NUP98-NSD1, and NUP98-HHEX (11-15).
EGR1
This is an immediate-early gene that encodes a zinc finger transcription
factor (16). It is upregulated in human AML with monocytic differentiation
(17) and in prostate cancer (18). It is also upregulated in a mouse model
of acute promyelocytic leukemia (19) and there is evidence that it
mediates the proliferative effects of erythropoietin on mouse
erythroblasts (20). These data suggest that upregulation of EGR1 by
NUP98 fusions may contribute to the leukemic transformation of primary
human cells, particularly to the increased numbers of erythroid cells
observed.
SOX4
This is a transcription factor that contains an HMG DNA-binding domain
(21). It can cooperate with either MEF2C or EVI1 to induce AML in mice
(22, 23) and is induced by the AML-associated RUNX1-ETO fusion
oncoprotein in primary human hematopoietic cells (24).
MYCN
This is a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription
factor that is well known for its amplification and overexpression in
neuroblastoma and other pediatric tumors (25). MYCN is also amplified
and overexpressed in lymphomas (26, 27). More recently, it was
reported that MYCN is overexpressed in many cases of pediatric AML
and that its overexpression in mice leads to the development of AML
(28). Therefore upregulation of MYCN may contribute to leukemic
transformation by NUP98 fusions.
ZNF521
Also known as EHZF, this is a zinc finger protein that is expressed in
primitive human CD34+ hematopoietic cells and declines with
differentiation (29). It is expressed in most cases of AML (29). It interacts
with of SMAD1, SMAD4, and GATA-1 and regulates their transcriptional
activity (29, 30). There is evidence that it inhibits erythroid differentiation
by inhibiting the transcriptional activity of GATA-1 (30).
HEY1
PTGS2
REN
This is a b-HLH protein also known as HERP2 that acts as a
transcriptional repressor. It is a mediator in the Notch signaling pathway
(31) and is implicated in the pathogenesis of tumors of the brain, lung,
pancreas, bone, skin, and kidney (32-37). Notch signaling is believed to
be important in the self-renewal of hematopoietic stem cells (38) and in
the pathogenesis of hematologic malignancies, particularly Tlymphoblastic leukemia (39). These data suggest that upregulation of
HEY1 may contribute to the long-term proliferation and increased
numbers of LTC-ICs induced by NUP98 fusions. HEY1 plays a role in
erythroid differentiation: in a mouse cell line, Notch signaling associated
with HEY1 upregulation increased the numbers of erythroid cells (40),
and upregulation of HEY1 by JUN in primary human hematopoietic cells
was associated with a block in erythroid differentiation (41). The
somewhat different results obtained in these two studies may reflect the
different experimental systems used, but the data nevertheless suggest
that the increased numbers of erythroid cells and the disrupted erythroid
differentiation that we observed in primary human cells expressing
NUP98 fusions may be mediated at least in part by upregulation of
HEY1.
This
gene
encodes prostaglandin-endoperoxide
synthase
2
(prostaglandin G/H synthase 2), better known as cyclooxygenase-2
(COX-2), which converts arachidonic acid to prostaglandins G2 and H2,
precursors of a number of different prostaglandins (42). COX-2 is
overexpressed in many tumors resulting in overproduction of
prostaglandins, including PGE2, which is thought to be important in
carcinogenesis (42). Many types of cancer overexpress COX-2 and its
inhibition with drugs such as aspirin can be used in the prevention and
treatment of cancer (43). A number of hematopoietic malignancies,
including chronic myleogenous leukemia, chronic lymphocytic leukemia,
lymphomas, and myeloma, show overexpression of COX-2, which is
associated with a worse prognosis (44). There is evidence that the use
of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is
associated with a lower incidence of lymphomas and acute leukemia
(45). In particular, NSAID use can reduce the risk of AML, particularly
the FAB M2 subtype (AML with maturation) (46), which is the most
common subtype in cases with NUP98 gene rearrangements (47). The
upregulation of PTGS2 by NUP98 fusions may contribute to the worse
prognosis of AML associated with NUP98 gene rearrangements, and
raises the possibility that COX-2 blockade could help in the treatment of
these leukemias.
This gene encodes renin, a constituent of the renin-angiotensin system
(RAS) that converts angiotensinogen to angiotensin I, which in turn is
converted by angiotensin-converting enzyme (ACE) to angiotensin II, a
regulator of blood pressure and electrolyte balance (48). In addition to
this role, the RAS may play an important role in hematopoiesis and AML
(49). Indeed, angiotensin II has been shown to increase the proliferation
of both primitive and committed hematopoietic progenitors (50, 51).
Blasts from many AML patients express renin while normal bone marrow
cells do not (52-54); in addition, angiotensinogen and ACE are also
expressed in bone marrow from AML patients (55). Thus it is possible
that the enhanced expression of renin is a part of the mechanism for
ANGPT1
RYK
STYK1
TMOD1
IDO2
uncontrolled cell growth in some leukemias. Interestingly, drugs that
inhibit the RAS system, including ACE inhibitors and losartan, have been
shown to inhibit growth and induce apoptosis in AML cell lines in vitro
(56). These data raise the possibility that such drugs may be useful in
the treatment of AML associated with NUP98 gene rearrangements.
Angiopoietin-1 is an angiogenic growth factor that is produced by
leukemic cells from AML patients (57). It is co-expressed with its
receptor, Tie2 (TEK), in AML cells and is thought to act as an autocrine
and paracrine factor that enhances angiogenesis and the growth of AML
cells (58-60).
This is a tyrosine kinase with an aberrant catalytic domain that acts as a
receptor in Wnt signaling (61). The WNT signaling pathway, particularly
the Wnt3a ligand, plays an important role in maintaining hematopoietic
stem cell function (62). RYK interacts with Wnt3a and mediates Wnt
signaling (63). It has been identified in maturing hematopoietic cells in
mice (64). Finally, RYK is overexpressed in ovarian cancer and is
capable of transforming mouse fibroblasts (65, 66).
Also known as NOK, this is a putative protein kinase that transforms cells
in vitro and promotes their tumorigenesis and metastasis in mice (67,
68). It is overexpressed in breast and lung cancer (69, 70).
This gene encodes tropomodulin 1, a member of the tropomodulin family
of proteins that cap the slow-growing pointed end of actin filaments (71).
Tropomodulin 1 is expressed in erythroid cells (71), and its upregulation
by NUP98 fusions likely reflects the increased numbers of erythroid cells
observed.
The first step in the catabolism of tryptophan is catalyzed by two related
indoleamine 2,3-dioxygenase enzymes, IDO and IDO2 (72). IDO is
expressed by many human tumors and by dendritic cells and is thought
to facilitate the escape of tumors from immune surveillance (73). An
inhibitor of indoleamine 2,3-dioxygenase enzymes, 1-methyl-tryptophan,
shows antitumor activity in mice (73). Interestingly, the D-isomer of 1methyl tryptophan, which preferentially inhibits IDO2, shows higher
antitumor activity than the L-isomer, which targets IDO (74, 75).
Downregulated genes:
RAP1A
This gene a small GTPase of the Ras family that was identified as a
suppressor of the transforming activity of oncogenic Ras in NIH/3T3 cells
(76). It was subsequently found to potentiate the functions of Ras in some
cells and to antagonize them in others (77). RAP1A functions in integrinmediated adhesion and signaling and in the MAP kinase cascade (77). It
plays various roles in the proliferation and differentiation of hematopoietic
cells (78). For example, megakaryocytic, monocytic, and lymphoid
differentiation of cell lines is associated with RAP1A induction (79, 80).
Maturation of megakaryocytes derived from human cord blood cells is also
associated with induction of RAP1A (81).
Thrombopoietin-induced
megakaryocytic differentiation is mediated by sustained activation of the
ERK/MAPK pathway mediated by RAP1A activation and inhibition of
megakaryocytic differentiation by stromal contact is associated with a
block in RAP1A activation (80, 82). Finally, RAP1A is activated by
erythropoietin (83), raising the possibility that it plays a role in erythroid
FCGR2C
CLEC7A
ALOX5
FPR3
A2M
ELA2
GADD45B
MS4A3
TRIM35
ZFHX3
differentiation. Based on these data, the repression of RAP1A expression
by both NUP98 fusions may play a role in their inhibition of both erythroid
and myeloid differentiation.
This is an isoform of FCGR2, also known as CD32. It is expressed on
myelomonocytic cells and is upregulated during myeloid differentiation
(84-87). Its downregulation by NUP98 fusions is consistent with the
observed disruption of myeloid differentiation.
This gene, also known as Dectin-1, encodes a beta-glucan receptor that is
expressed on myeloid cells including monocytes/macrophages,
neutrophils, and eosinophils (88-90). Its repression by NUP98 fusions
may reflect disruption of myeloid differentiation.
This is a member of the lipoxygenase gene family that plays a role in the
synthesis of leukotrienes from arachidonic acid. It is transcriptionally
upregulated during myeloid differentiation (91-93). Its repression by
NUP98 fusions likely reflects disrupted myeloid differentiation.
This is a member of the family of formyl peptide receptors; it is also known
as FPRL2 and expressed in monocytes (94). Its repression by NUP98
fusions may reflect disrupted myeloid differentiation.
This gene encodes the protease inhibitor alpha-2-macroglobulin, which is
induced during the maturation of monocytes to macrophages (95, 96). Its
repression by NUP98 fusions may reflect disrupted myeloid differentiation.
This gene encodes elastase, a component of neutrophil granules (97). Its
downregulation by NUP98 fusions is consistent with their disruption of
myeloid differentiation.
Also known as MyD118, this is one of a closely related family of genes
associated with terminal myeloid differentiation and involved in the
induction of cell cycle arrest and apoptosis (98). Its early downregulation
by NUP98 fusions may contribute to blocked differentiation and increased
proliferation.
This gene, also known as HTm4, belongs to a family of proteins with 4
membrane-spanning domains and is expressed predominantly in
hematopoietic cells (99). It is involved in the regulation of the cell cycle in
hematopoietic cells where its overexpression leads to cell cycle arrest at
the G0/G1 phase (100). Repression of the myeloid oncogene AML1-ETO
in cell lines and primary AML blasts results in induction of MS4A3 (101),
indicating that the proliferative effects of AML1-ETO are mediated by
downregulation of MS4A3.
Also known as Hls5 or MAIR, this gene is thought to act as a tumor
suppressor that induces apoptosis and is associated with erythroid-tomyeloid lineage switch (102-104). Its repression by NUP98 fusions may
explain the skewing towards erythroid differentiation (Figure 3); it also
raises the possibility that the increased numbers of cells in long-term
culture (Figure 2) may be due in part to decreased apoptosis.
This gene is also known as ATBF1 and encodes two isoforms of a
transcription factor that contains multiple homeodomains and zinc fingers
(105, 106).
It is thought to act as a tumor suppressor that is
downregulated in cancers of the prostate, breast, liver, and stomach (107110). In neuronal cells, it induces differentiation and cell cycle arrest
(111). Based on these findings, it is possible that downregulation of
ZFHX3 by NUP98 fusions plays a role in their ability to block differentiation
NDRG2
RAD18
EED
GPX3
and induce proliferation in hematopoietic cells.
This is a member of the N-myc downregulated gene family. It is thought to
act as a tumor suppressor that is downregulated in many tumors including
carcinomas of the colon and thyroid, glioblastoma, and others (112-116).
Its repression by NUP98 fusions suggests a similar role as a tumor
suppressor in AML.
This gene encodes a ubiquitin ligase involved in DNA repair (117, 118).
Its downregulation by NUP98 fusions may predispose cells to further DNA
damage. For example in patients treated with topoisomerase II inhibitors,
who are susceptible to NUP98 gene rearrangements (47), such a
mechanism may lead to additional mutations that could cooperate with the
NUP98 fusion in producing AML.
This is one of the Polycomb Group (PcG) gene that act as transcriptional
repressors (119). Two Polycomb repressive complexes (PRC) have been
described: PRC1 and PRC2. EED is a component of the PRC2 complex
that methylates H3K27 and represses the expression of several HOX
genes (119, 120). Interestingly, several HOX genes including HOXA7,
HOXA9, MEIS1, and others are upregulated by NUP98 fusions
(Supplementary Tables S6 – S8). This upregulation of HOX genes may
be explained at least in part by repression of EED.
This gene encodes glutathione peroxidase 3, a selenium dependent
enzyme that plays a role in detoxifying reactive oxygen species and is
downregulated in a number of cancers including those of the prostate,
esophagus, and stomach (121-125). Its reression by NUP98 fusions
suggests that it may play a role in AML as well.
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