Development of molecular intervention strategies for B-cell lymphoma

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Figure 1. TP53 pathway

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; ROS, oxygen species; IAP, inhibitor of apoptosis protein; 1. DNA damage anti-cancer drugs can effectively stimulate the apoptosis of hematopoietic cells, and the main mediator of apoptosis induced by genotoxic pressure is p53 [4]; 2. P53 in the cytoplasm is also related to mitochondria, which can directly induce the activity of Bax and inhibit the activities of BCL-2 and BCL-XL [7]; 3. Caspases are an apoptotic protease, while IAP is its antagonistic protein; 4. P53 protein is a tetramer transcription factor, and its expression level is controlled by E3 ligase MDM2. ATM, Ataxia telangiectasia mutant protein kinase; ATR, ataxia telangiectasia and rad3 related kinase; CDK, cyclin-dependent kinases.

Table 1. Therapeutic modulation of the TP53 pathway [4]

Mechanisms	Target	Drugs
Induction and activation of p53 by stress within the nucleus	Alkylating agents	Chlorambucil
	DNA-intercalating agents	Doxorubicin
	ROS	Combined cisplatin and fludarabine
	Inhibitor of the nuclear export protein XPO1	Selinexor
Activation of the extrinsic apoptotic pathway	TRAIL inhibitors	Agonistic TRAIL-R2/DR5 mAB (lexatumumab, AMG 655)
Enhancement of the intrinsic mitochondrial pathway of apoptosis	BCL-2 and IAP family members	GX15-003, GX15-070, ABT-737/263, AT-101,
	Activating caspases or BAX/BAK	SAHBs
Antagonism of MDM2-mediated	MDM4 inhibitors	XI-011
	MDM2 inhibitor	Nutlin-3a, idasanutlin

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; ROS, reactive oxygen species; IAP, inhibitor of apoptosis protein

1. DNA damage anti-cancer drugs can effectively stimulate the apoptosis of hematopoietic cells, and the main mediator of apoptosis induced by genotoxic pressure is p53 [4]; 2. P53 in the cytoplasm is also related to mitochondria, which can directly induce the activity of Bax and inhibit the activities of BCL-2 and BCL-XL [7]; 3. Caspases are an apoptotic protease, while IAP is its antagonistic protein; 4. P53 protein is a tetramer transcription factor, and its expression level is controlled by E3 ligase MDM2.

Figure 2. Role of EZH2 in tumorigenesis. SAM, S-adenosyl-l-methionine

Table 2. Current clinical trials with investigational EZH2 inhibitors in B-cell lymphoma

Novel Agent	Clinical Trial No.	Clinical Trial Phase	Additional Remarks
Tazemetostat	NCT01897571	Phase I (closed); Phase II (recruiting)	Phase I preliminary results: Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumors [20].
GSK2816126	NCT02082977	Phase I (recruiting)	Unreasonable grouping. Outcome data is not available [24].
CPI-1205	NCT02395601	Phase I (recruiting)	Outcome data not available.

Figure 3. BCL-2 family proteins

BCL-2 family proteins include anti-apoptotic proteins (BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1, BCL-B) and pro-apoptotic proteins (Bad, Bid, Bax, Bok). In addition, BCL-2 homologous 3 (BH3)-specific sensitizers (Bad, Bik, Bim, Hrk, BCL-GS, p193, APR (Noxa and PUMA); BH3-specific activators (such as Noxa, PUMA, Bid) can not only play the role of death activators with apoptotic proteins (Bax, Bak) but also dimerize with anti-apoptotic proteins (such as BCL-2, BCL-x), further inhibiting the activity of survivin. Bax/Bak can induce mitochondrial outer membrane permeability (MOMP), which cannot only release mitochondrial death-inducing protein but also further induce necrosis through oxidative phosphorylation [38]

Table 3. BCL-2 inhibitors and current clinical status

Name	Proposed main targets	Development status
ABT‐199/Venetoclax [28]	BCL-2	FDA Approved
ABT‐263/navitoclax [29]	BCL-2, BCL‐XL, BCL-w	Clinical Trial
ABT‐737 [30]	BCL-2, BCL‐XL, BCL-w
Gossypol/AT101 [31]	pan‐BCL-2	Clinical Trial
WEHI‐539 [32]	BCL‐XL
A1331852 and A1155463 [33,34]	BCL‐XL
UMI‐77 [35]	MCL1
S63845 [36]	MCL1
TW37 [37]	BCL2, BCL‐XL, MCL1

Figure 4. MYD88 pathway(CBM complex, CARD11/BCL-10/MALT1)

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