4.2.1 Myeloid Malignancies
Myeloid malignancies are stem cell-derived clonal disorders and comprise three
different categories: acute myeloid leukemia (AML), myelodysplastic syndrome
(MDS), and myeloproliferative neoplasms (MPN). Both PDGFR-α (gene PDGFRA
located on chromosome 4q12) and β (gene PDGFRB located on chromosome 5q31–
q32) are linked to myeloid malignancies [141]. In 1994, a fusion protein containing
the tyrosine kinase domain of PDGFR-β (tel-PDGFRβ) was associated with a
subtype of MDS, i.e., the chronic myelomonocytic leukemia (CMML)
[141, 142]. Later, in 2003, a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRA
gene generated by an interstitial deletion on chromosome 4q12 was identified as a
marker of the hypereosinophilic syndrome, a rare hematologic disorder with
sustained overproduction of eosinophils in the bone marrow [143]. Moreover, the
FIP1L1-PDGFRA fusion gene was also identified in rare cases of acute myeloid
leukemia and T-cell acute lymphoblastic leukemia [144]. The generated fusion
protein FIP1L1-PDGFR-α is constitutively activated [143].
4.2.2 Gastrointestinal Stromal Tumors (GISTs)
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors
of the gastrointestinal tract, most of them (~80%) presenting activating mutations in
the c-KIT receptor tyrosine kinase [145–147]. Around 50% of GISTs are metastatic,
usually to liver or peritoneum [148]. In 2003, a study from Heinrich and coworkers
demonstrated that around 40% of GISTs lacking c-KIT mutations present activation
mutations in a related receptor tyrosine kinase, i.e., PDGFR-α, indicating that
mutations in these RTKs represent mutually exclusive oncogenic mechanisms in
GISTs. Moreover, these authors concluded that tumors expressing c-KIT or
PDGFR-α oncoproteins were indistinguishable regarding the activation of downstream signaling pathways [147, 149].
Among PDGFRA-mutated patients, the most common mutation (~60%) was
located in the exon 18, producing an activation loop with a valine instead of the
conserved aspartic acid at codon 842 (PDGFR-α D842V) [145, 147, 149]. Another
gain-of-function mutation of PDGFR-α in GIST was described by Hirota et al. [150],
comprising the substitution of Val-561 to Asp (PDGFR-α V561D) at the
juxtamembrane domain (exon 12). These authors also demonstrated that mutated
PDGFR-α D842V and V561D represent constitutively activated forms of this RTK
[150]. From then on, several other PDGFR-α mutations affecting the activation loop
(exon 18), the juxtamembrane domain (exon 12), or the tyrosine kinase domain
(exon 14) have been described for GIST patients [145].
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L. M. Lima et al.
Myeloid malignancies are stem cell-derived clonal disorders and comprise three
different categories: acute myeloid leukemia (AML), myelodysplastic syndrome
(MDS), and myeloproliferative neoplasms (MPN). Both PDGFR-α (gene PDGFRA
located on chromosome 4q12) and β (gene PDGFRB located on chromosome 5q31–
q32) are linked to myeloid malignancies [141]. In 1994, a fusion protein containing
the tyrosine kinase domain of PDGFR-β (tel-PDGFRβ) was associated with a
subtype of MDS, i.e., the chronic myelomonocytic leukemia (CMML)
[141, 142]. Later, in 2003, a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRA
gene generated by an interstitial deletion on chromosome 4q12 was identified as a
marker of the hypereosinophilic syndrome, a rare hematologic disorder with
sustained overproduction of eosinophils in the bone marrow [143]. Moreover, the
FIP1L1-PDGFRA fusion gene was also identified in rare cases of acute myeloid
leukemia and T-cell acute lymphoblastic leukemia [144]. The generated fusion
protein FIP1L1-PDGFR-α is constitutively activated [143].
4.2.2 Gastrointestinal Stromal Tumors (GISTs)
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors
of the gastrointestinal tract, most of them (~80%) presenting activating mutations in
the c-KIT receptor tyrosine kinase [145–147]. Around 50% of GISTs are metastatic,
usually to liver or peritoneum [148]. In 2003, a study from Heinrich and coworkers
demonstrated that around 40% of GISTs lacking c-KIT mutations present activation
mutations in a related receptor tyrosine kinase, i.e., PDGFR-α, indicating that
mutations in these RTKs represent mutually exclusive oncogenic mechanisms in
GISTs. Moreover, these authors concluded that tumors expressing c-KIT or
PDGFR-α oncoproteins were indistinguishable regarding the activation of downstream signaling pathways [147, 149].
Among PDGFRA-mutated patients, the most common mutation (~60%) was
located in the exon 18, producing an activation loop with a valine instead of the
conserved aspartic acid at codon 842 (PDGFR-α D842V) [145, 147, 149]. Another
gain-of-function mutation of PDGFR-α in GIST was described by Hirota et al. [150],
comprising the substitution of Val-561 to Asp (PDGFR-α V561D) at the
juxtamembrane domain (exon 12). These authors also demonstrated that mutated
PDGFR-α D842V and V561D represent constitutively activated forms of this RTK
[150]. From then on, several other PDGFR-α mutations affecting the activation loop
(exon 18), the juxtamembrane domain (exon 12), or the tyrosine kinase domain
(exon 14) have been described for GIST patients [145].
184
L. M. Lima et al.