Table 1.

Key transcription factors for platelet biogenesis and mutations found in inherited platelet disorders.

Transcription Factor	Target Genes	Alterations of Megakaryopoiesis	Defects in Platelet Function	Disease	Other Features	Ref
RUNX1	PF4, NR4A3, PRKCQ, MYL9	Reduced polyploidization and proplatelet formation	Platelet granule deficiency	Familial platelet disorder with a predisposition to myeloid malignancy (FPDMM)	High risk (>40%) of acute myeloblastic leukemia or MDS at a young age, Absent to moderate bleeding tendency	[76,77,78]
GATA1	NFE2, ITGA2B, Erythropoietic genes (ALAS2, BCL2L1, etc.)	Dysplasia of immature MK and MEP	Platelet alpha granule deficiency, Macrothrombocytopenia, Impaired platelet aggregation	GATA1-related disorders	Dyserythropoiesis with or without anemia, Risk of TMD, DS-AMKL	[79,80,81]
FLI1	MPL, ITGA2B, PF4, GP9	Dysmegakaryopoiesis, Reduced MK production from the patient-derived iPSCs	Macrothrombocytopenia with giant fused alpha granules, Defective platelet aggregation	Paris-Trousseau syndrome (PTS), FLI1-related thrombocytopenia, Jacobsen syndrome	Risk of bleeding	[82,83]
NFE2	TUBB1, RAB27b, CASP12, HSD3B1	Hyperplasia of immature MKs, Impaired DMS in MKs, Lack of binding activity to fibrinogen	Decreased levels of circulating platelets in Nfe2-null mice	Patients with MPNs show upregulation of NFE2 regardless of the presence of JAK2 mutation	Anemia with compensatory reticulocytosis and splenomegaly in Nfe2-null mice	[84,85,86]
MECOM	MPL	Hypomegakaryopoiesis	Severe bleeding tendency	MECOM-related thrombocytopenia	Bone marrow failure, Elevated TPO levels in plasma, Anemia, B-cell deficiency	[87,88,89]
ETV6	GP1BA, GPIX	Hyperplasia of immature MKs, Dyserythropoiesis, Increased number of circulating HSPCs	Elongated alpha granules in platelets, Impaired adhesion, spreading and clot retraction activity	ETV6-related thrombocytopenia	Leukemia predisposition, Platelets with high levels of transcripts for erythrocytes, Absent to mild bleeding	[90,91,92]
GFI1B	RGS18	Hyperplasia of MK and MkPs	Macrothrombocytopenia, Alpha granule deficiency, Defects in platelet aggregation, Reduced expression of GP1ba	GFI1B-related thrombocytopenia (GFI1B-RT)	Anisocytosis and poikilocytosis of RBCs, Mild to severe bleeding, Dyserythropoiesis, Severe phenotypes in mice model	[93,94,95]
IKZF5	Platelet activation genes (LYN, P2RY12, etc.)	N/A	Platelets with reduced alpha and delta granules	IKZF5-related thrombocytopenia	Downregulation of gene expression for platelet biogenesis including GATA1, No bleeding tendency	[96]

RUNX1, Runt-related transcription factor 1; PF4, Platelet Factor 4; NR4A3, Nuclear Receptor subfamily 4 group A member 3; PRKCQ, Protein Kinase C theta; MYL9, Myosin Light Chain 9; MDS, Myelodysplastic Syndrome; NFE2, Nuclear Factor Erythroid 2; ITGA2B, Integrin αIIb; ALAS2, 5′-Aminolevulinate Synthase 2; BCL2L1, BCL2 Like 1; MEP, Megakaryocyte-Erythroid Progenitor; TMD, Transient Myeloproliferative Disorder; DS-AMKL, Down Syndrome Acute Megakaryoblastic Leukemia; FLI1, Friend Leukemia virus Integration 1; MPL, thrombopoietin receptor; iPSC, induced Pluripotent Stem Cell; TUBB1, Tubulin Beta 1; CASP12, Caspase 12; HSD3B1, 3-beta-Hydroxysteroid Dehydrogenase; DMS, Demarcation System; MECOM, MDS1 and EVI1 Complex Locus; ETV6, ETS Variant 6; HSPC, Hematopoietic Stem and Progenitor Cell; RGS18, Regulator of G protein Signaling 18; RBC, Red Blood Cell; P2RY12, P2Y Purinoceptor 12; N/A, Not Applicable.