AKT
Encyclopedia
Akt, also known as Protein Kinase
B (PKB), is a serine
/threonine
protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis
, transcription and cell migration.
, Akt2
, and Akt3
. These genes code for enzyme
s that are members of the Non-specific serine/threonine protein kinase
family .
Akt1 is involved in cellular survival pathways, by inhibiting apoptotic
processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene
in the transforming retrovirus
, AKT8.
Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance
), again consistent with the idea that Akt2 is more specific for the insulin receptor
signaling pathway.
The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains.
known as a PH domain, or Pleckstrin Homology domain
, named after Pleckstrin
, the protein in which it was first discovered. This domain binds to phosphoinositides
with high affinity. In the case of the PH domain of Akt, it binds either PIP3 (phosphatidylinositol (3,4,5)-trisphosphate
, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate
, PtdIns(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PIP2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase
or PI3-K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase
such as the insulin receptor
. Once activated, PI 3-kinase phosphorylates PIP2 to form PIP3.
molecule, although other molecules, including Integrin-linked kinase
(ILK) and Mitogen-Activated Protein Kinase Activated Protein Kinase-2 (MAPKAPK2
) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDPK1.
Activated Akt can then go on to activate or deactivate its myriad substrates (eg mTOR) via its kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt may possibly also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP
-elevating agents could activate Akt through protein kinase A (PKA) in the presence of insulin, although these studies are disputed and the mechanism of action is unclear.
PTEN
, which works essentially as the opposite of PI3K mentioned above. PTEN acts as a phosphatase
to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do all of the downstream pathways that depend on Akt for activation.
PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1
and SHIP2
. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2.
family, PHLPP1
and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3.
by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2
).
Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD
is a pro-apoptotic protein of the Bcl-2
family. Akt could phosphorylate BAD on Ser136, which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function. Akt could also activate NF-κB via regulating IκB kinase
(IKK), thus result in transcription of pro-survival genes.
. Under various circumstances, activation of Akt was shown to overcome cell cycle arrest in G1 and G2 phases. Moreover, activated Akt may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes.
) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3
) could be inhibited upon phosphorylation by Akt, which results in increase of glycogen synthesis. GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway.
Still unknown role in HCV
induced steatosis
.
and tumor development. Although deficiency of Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels.
Because of the Akt[1] functions above Akt inhibitors may treat cancers such as neuroblastoma
. Some Akt inhibitors have undergone clinical trials. In 2007 VQD-002 had a phase I trial.
In 2010 Perifosine
has reached phase II.
Miltefosine
is approved for leishmaniasis
and under investigation for other indications including HIV.
AKT activation is associated with many malignancies, however, a research group from Massachusetts General Hospital
and Harvard University
unexpectedly observed a converse role for AKT and one of its downstream effector FOXOs in acute myeloid leukemia
(AML). They claimed that low levels of AKT activity associated with elevated levels of FOXOs are required to maintain the function and immature state of leukemia-initiating cells (LICs). FOXOs are active, implying reduced Akt activity, in ∼40% of AML patient samples regardless of genetic subtype; and either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth in mouse model.
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
B (PKB), is a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
/threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, transcription and cell migration.
Family members
In humans, there are three genes in the "Akt family": Akt1AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
, Akt2
AKT2
RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.-Interactions:AKT2 has been shown to interact with TCL1A, APPL1, SH3RF1 and CHUK.-Further reading:...
, and Akt3
AKT3
RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT3 gene.-Interactions:AKT3 has been shown to interact with Protein kinase Mζ.-Further reading:...
. These genes code for enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that are members of the Non-specific serine/threonine protein kinase
Non-specific serine/threonine protein kinase
In enzymology, the term non-specific serine/threonine protein kinase describes a class of enzymes that belong to the family of transferases, specifically protein-serine/threonine kinases. These enzymes transfer phosphates to the oxygen atom of a serine or threonine sidechain in proteins. This...
family .
Akt1 is involved in cellular survival pathways, by inhibiting apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
in the transforming retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
, AKT8.
Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce glucose transport. In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
), again consistent with the idea that Akt2 is more specific for the insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
signaling pathway.
The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains.
Name
The name Akt does not refer to its function. Presumably, the "Ak" in Akt was a temporary classification name for a mouse strain developing spontaneous thymic lymphomas. The "t" stands for 'transforming' (no; 'thymoma' - see Discussion), the letter was added when a transforming retrovirus was isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly.Binding phospholipids
Akt possesses a protein domainProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
known as a PH domain, or Pleckstrin Homology domain
Pleckstrin homology domain
Pleckstrin homology domain is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton....
, named after Pleckstrin
Pleckstrin
Pleckstrin is a protein found in platelets. The name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids.It is the source of the name pleckstrin homology domain....
, the protein in which it was first discovered. This domain binds to phosphoinositides
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
with high affinity. In the case of the PH domain of Akt, it binds either PIP3 (phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
, PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
, PtdIns(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PIP2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
or PI3-K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
such as the insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
. Once activated, PI 3-kinase phosphorylates PIP2 to form PIP3.
Phosphorylation
Once correctly positioned at the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide dependent kinase 1 (PDPK1 at threonine 308) and mTORC2 (at serine 473). First, the mammalian target of rapamycin complex 2 (mTORC2); mTORC2 therefore functionally acts as the long-sought PDK2PDK2
Pyruvate dehydrogenase kinase isoform 2 also known as [pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase....
molecule, although other molecules, including Integrin-linked kinase
Integrin-linked kinase
Integrin-linked kinase is a 59kDa protein originally identified while conducting a yeast-two hybrid screen with integrin β1 as the bait protein...
(ILK) and Mitogen-Activated Protein Kinase Activated Protein Kinase-2 (MAPKAPK2
MAPKAPK2
MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.-Interactions:MAPKAPK2 has been shown to interact with MAPK14, AKT1, PHC2 and SHC1.-Further reading:...
) can also serve as PDK2. Phosphorylation by mTORC2 stimulates the subsequent phosphorylation of Akt by PDPK1.
Activated Akt can then go on to activate or deactivate its myriad substrates (eg mTOR) via its kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt may possibly also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
-elevating agents could activate Akt through protein kinase A (PKA) in the presence of insulin, although these studies are disputed and the mechanism of action is unclear.
Lipid phosphatases and PIP3
PI3K dependent Akt activation can be regulated through the tumor suppressorTumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
PTEN
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
, which works essentially as the opposite of PI3K mentioned above. PTEN acts as a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do all of the downstream pathways that depend on Akt for activation.
PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases, SHIP1
INPP5D
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.-Interactions:INPP5D has been shown to interact with DOK2, LYN, CD22, Grb2, CRKL, CD31, DOK1 and SHC1.-Further reading:...
and SHIP2
INPPL1
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 is an enzyme that in humans is encoded by the INPPL1 gene.-Interactions:INPPL1 has been shown to interact with BCAR1, SORBS1, FLNC and SHC1.-Further reading:...
. These poly-phosphate inositil phosphatases dephosphorylate PtdIns(3,4,5)P3 to form PtdIns(3,4)P2.
Protein phosphatases
The phosphatases in the PHLPPPHLPP
The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, which are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C isoforms...
family, PHLPP1
PHLPP
The PHLPP isoforms are a pair of protein phosphatases, PHLPP1 and PHLPP2, which are important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C isoforms...
and PHLPP2 have been shown to directly de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3.
Function
Akt regulates cellular survival and metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
).
Cell survival
Bcl-2-associated death promoter
The Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family...
is a pro-apoptotic protein of the Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family. Akt could phosphorylate BAD on Ser136, which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function. Akt could also activate NF-κB via regulating IκB kinase
IκB kinase
The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation.The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade...
(IKK), thus result in transcription of pro-survival genes.
Cell Cycle
Akt is known to play a role in the cell cycleCell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Under various circumstances, activation of Akt was shown to overcome cell cycle arrest in G1 and G2 phases. Moreover, activated Akt may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes.
Metabolism
Akt2 is required for the insulin-induced translocation of glucose transporter 4 (GLUT4GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3
GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
) could be inhibited upon phosphorylation by Akt, which results in increase of glycogen synthesis. GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway.
Still unknown role in HCV
Hepatitis C virus
Hepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...
induced steatosis
Steatosis
In cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...
.
Angiogenesis
Akt1 has also been implicated in angiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and tumor development. Although deficiency of Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels.
Clinical relevance
Akt is associated with tumor cell survival, proliferation, and invasiveness. The activation of Akt is also one of the most frequent alterations observed in human cancer and tumor cells. Tumor cells that have constantly active Akt may depend on Akt for survival. Therefore, understanding Akt and its pathways is important for the creation of better therapies to treat cancer and tumor cells. A mosaic activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with the Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other tissuesBecause of the Akt[1] functions above Akt inhibitors may treat cancers such as neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
. Some Akt inhibitors have undergone clinical trials. In 2007 VQD-002 had a phase I trial.
In 2010 Perifosine
Perifosine
Perifosine is a drug candidate being developed for a variety of cancer indications.It is an alkylphospholipid Perifosine is structurally related to miltefosine...
has reached phase II.
Miltefosine
Miltefosine
Miltefosine is a phospholipid drug.Originally developed as an antineoplastic , it is finding use as an antiprotozoal drug...
is approved for leishmaniasis
Leishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
and under investigation for other indications including HIV.
AKT activation is associated with many malignancies, however, a research group from Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
and Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
unexpectedly observed a converse role for AKT and one of its downstream effector FOXOs in acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
(AML). They claimed that low levels of AKT activity associated with elevated levels of FOXOs are required to maintain the function and immature state of leukemia-initiating cells (LICs). FOXOs are active, implying reduced Akt activity, in ∼40% of AML patient samples regardless of genetic subtype; and either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth in mouse model.