Wilms’ tumor gene 1 in hematological malignancies: friend or foe?

Figures & data

Figure 1. Schematic of the WT1 structure.

Table 1. The clinical findings of WT1.

Year	Story
1899	A tumor suppressor gene, first identified in Wilms’ tumor [1,2].
1992	High expression in human leukemia [127].
1999	High expression in solid tumor cell lines [128].
2000	The mice that sufferred WT1 immunotherapy survived for a long time [129].
2004	WT1 vaccination could result in breast or lung cancer and leukemia regression [130].
2009	Among 75 malignant tumor antigens with high potential for immunotherapy, WT1 has been ranked first by the National Cancer Institute pilot Project [131].

Table 2. Correlation between WT1 mutations/overexpression and clinical characteristics.

Disease		AML		ALL	MDS
Group		WT1^MT vs. WT1^WT	High-WT1 vs. Low-WT1	High-WT1 vs. Low-WT1	High-WT1 vs. Low-WT1
Correlation	Positive	Younger [7,132]; WBCs and BM [7]; Blast percentages [7]; Cytogenetic normal, FLT3^ITD, biallelic CEBPA mutations, primary AML (85%) and female patients [7,40].	Older [8,9,63,64,133]; CD34 + cells [8,9,61,133]; WBCs [61,63,65]; BM or PB blasts [8,9,62,65]; The frequency of FLT3^ITD+ [8,62–65]; NPM1 mutations [62,64,65,71,133]; M2, M3 and M4 [8,9,37,43,59,63,133]; High-risk cytogenetics [9,64]; CD117, CD123 and CD13 expression (in intermediate and poor cytogenetic risk AML) [133].	Pro-ALL [86–88]; KMT2A rearrangement [86]; aberrant expression of Myeloid markers [87]; Younger [88]; WBCs > 50 × 10^9/g at diagnosis, the high-risk group, t(4;11) or MRD(+)[87,88].	CD34 + cells, normalized blast counts and BM blasts [61]; BM/PB blasts, aberrant or complex karyotypes [95]; Younger [95]; Poor prognostic chromosomal rearrangements [93].
	Negative	Platelet counts[7].	Hb levels [8,63,65]; CEBPA^dm, RUNX1-ETO fusion gene [43,71]; Myeloid differentiation-related and lymphoid markers (in intermediate and poor cytogenetic risk AML) [133].	BCR-ABL1 fusion [86]	Platelet counts and granulocytecounts [61,95].
	Controversy or No difference	_	Platelet counts [8,9,61,63,65]; Sex [8,9,62–65,133]; Complex karyotypes [8,63,64].	Sex, age, Hb levels, leukocyte counts and BM blasts [86–88].	WBCs, Sex and Hb levels [61,95].

Table 3. Trials associated with immune therapy of WT1 in recent years.

Research	Interventions	Phase (clinicaltrials.gov)	Experiment objects	Country	Efficacy assessments
Plantinga [109]	WT1-loaded cord blood-derived dendritic cell	Pre-clinical	Pediatric AML primary cells	England	Migration and allogeneic T-cell activation; surface LAMP-1 expression and intracellular IFNg expression.
Almshayakhchi [110]	HAGE/WT1-immunobody (R)	Pre-clinical	Human CML cell lines; HDII/DR1 double transgenic mice	England	Peptide-binding affinity and stability; immunogenicity; CTLs; cytotoxicity; phenotypical characterization.
Augsberger [10]	RMF-peptide-MHC-specific T-cell- bispecific antibody	Pre-clinical	AML cells, mouse models	Germany	T-cell Cytotoxicity; downstream TCR signaling; T-cell activation and expansion; IFN-γ secretion and granzyme B secretion; lysis of healthy bone-marrow-derived CD34+; tumor burden; the number of CD45 + CD33 + cells.
Spira [113]	DSP-7888, WT1 peptide vaccine	I; NCT02498665	Patients with recurrent or advanced malignancies	America	Safety, tolerability, and identification of the recommended phase II dose; OS and WT1-specific CTL induction.
Kiguchi [117]	OCV-501, WT1 peptide vaccine	II;NCT01961882	Elderly AML patients	Multicenter (Japan, Korea, and Taiwan)	Immune responders; efficacy and safety; DFS, OS.
Kim [125]	WT1-CTLs	I/II	High-risk AML patients	Korea	CD8 + and CD4+ T cells; IFN-γ; clinical status; the PB lymphocyte subpopulations; WT1 mRNA expression levels.
Maslak [114]	Galinpepimut-S(GPS, WT1 peptide vaccine	II;NCT01266083	Adults AML patients	America	OS, DFS; CD4+ T cell proliferation, IFN-γ release, CD8+ T-cell response; WT1 mRNA levels.
Anguille [115]	WT1 mRNA-electroporated DC vaccines	II; NCT00965224	High-risk AML	Belgium	Clinical response; survival; immune responses.
Chapuis [112]	WT1-specific CD8 CTLs and low-dose IL-2	NCT00052520	Post-HCT patients (AML, MDS, or ALL)	America	Side effects, tolerability, GVHD, safety; persistence; preferential location; anti-leukemic activity.
Chapuis [121]	EBV-specific TTCR-C4	_	Poor-risk AML patients	America	Relapse-free survival (RFS), OS, relapse and non-relapse mortality (NRM); tolerability; persistence.
Ueda [134]	WT4869, WT1 peptide vaccine	I/II; Japiccti-101374	MDS patients	Japan	Safety; efficacy; biomarkers.

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