1. Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view
by Aaron D. Schimmer, David W. Hedley, Linda Z. Penn, and Mark D. Minden
Blood
Volume 98(13):
December 15, 2001
©2001 by American Society of Hematology

2. Mechanisms of multidrug resistance.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

3. Pathways of apoptosis.Two major pathways of apoptosis have been discerned—the receptor- and mitochondrial-mediated pathways.
Pathways of apoptosis.Two major pathways of apoptosis have been discerned—the receptor- and mitochondrial-mediated pathways. Both pathways culminate in the activation of caspase-3, a major downstream effector caspase. A third minor pathway has also been identified, whereby Granzyme B directly activates caspase-3.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

4. Activation of apoptosis through the TNF family of death receptors
Activation of apoptosis through the TNF family of death receptors.Activated Fas and TNFR-1 launch the receptor-mediated pathway of apoptosis by recruiting the adapter protein Fadd/Mort-1.
Activation of apoptosis through the TNF family of death receptors.Activated Fas and TNFR-1 launch the receptor-mediated pathway of apoptosis by recruiting the adapter protein Fadd/Mort-1. In turn, caspase-8 is activated, which cleaves procaspase-3. These receptors also induce apoptosis through an alternate pathway. Through adapter proteins TRADD and TRAF, a phosphorylation cascade is initiated, leading to the activation of JNK. Activated JNK phosphorylates substrates such as p53 and c-Jun, which leads to apoptosis through multiple mechanisms including regulating the Bcl-2 family of proteins.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

5. Activators of mitochondrial-mediated apoptosis
Activators of mitochondrial-mediated apoptosis.Many diverse triggers initiate the mitochondrial-mediated pathway of apoptosis.
Activators of mitochondrial-mediated apoptosis.Many diverse triggers initiate the mitochondrial-mediated pathway of apoptosis. These triggers have been classified as activators, intermediates, and effectors, depending on how directly they impact mitochondrial function. The pathways are complex, as a single activator can unleash multiple intermediates that in turn disrupt the mitochondria though multiple effectors.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

6. Electron transport in the mitochondria.(A) Electron transport chain.
Electron transport in the mitochondria.(A) Electron transport chain. The conversion of glucose to energy in the Krebs cycle requires the reduction of NAD+ to NADH. The reoxidization of NADH occurs through the electron transport chain in the inner mitochondrial membrane. The reaction can be summarized as NADH + H+ + 1/2O2 → NAD+ + H20. (B) ATP and H+flux across the mitochondrial membranes. The reoxidization of NADH to NAD+ in the electron transport chain produces H20 and releases energy. This energy is used to drive the production of ATP in the mitochondrial matrix. The adenine nucleotide transporter (Ant) controls the flux of ADP and ATP across the inner mitochondrial membrane. The voltage dependent anion channel (VDAC) regulates the flux of ATP across the outer mitochondrial membrane. Damage to VDAC or ANT can induce cytochrome c–release and initiate the mitochondrial-mediated pathway of apoptosis. Damage to ANT is also accompanied by physical mitochondrial swelling and loss of ΔΨM.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

7. Family of Bcl-2 proteins
Family of Bcl-2 proteins.The proteins in the Bcl-2 family of proteins are grouped based on their proapoptotic or antiapoptotic functions and their common Bcl-2 homology (BH) domains.
Family of Bcl-2 proteins.The proteins in the Bcl-2 family of proteins are grouped based on their proapoptotic or antiapoptotic functions and their common Bcl-2 homology (BH) domains. Some members also share common transmembrane (TM) and loop domains.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

8. The BH3 domains of the Bcl-2 family of proteins
The BH3 domains of the Bcl-2 family of proteins.The BH3 death domain is common to all members of the Bcl-2 family.
The BH3 domains of the Bcl-2 family of proteins.The BH3 death domain is common to all members of the Bcl-2 family. This domain contains a core sequence of 8 amino acids (core homology region). Within this region, amino acids 1 and 6 are critical for heterodimerization between family members.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology

9. Prototypic therapeutic agents for treatment of acute leukemia
Prototypic therapeutic agents for treatment of acute leukemia.TNF indicates tumor necrosis factor; TRAIL; PKC, protein kinase C; and AKT.
Prototypic therapeutic agents for treatment of acute leukemia.TNF indicates tumor necrosis factor; TRAIL; PKC, protein kinase C; and AKT.
Aaron D. Schimmer et al. Blood 2001;98:
©2001 by American Society of Hematology