Upload
shanon
View
21
Download
6
Embed Size (px)
DESCRIPTION
E2A and its Role in pre-B cell ALL. Allison Person 3-16-04. Acute Lymphoblastic Leukemia (ALL). Lymphocytes affected Bone marrow makes too many lymphocytes that do not mature correctly Crowding out of other normal blood cells Immature lymphocytes do not fight infection properly. - PowerPoint PPT Presentation
Citation preview
E2A and its Role in pre-B cell E2A and its Role in pre-B cell ALLALL
Allison Person Allison Person
3-16-043-16-04
Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia (ALL)(ALL)
Lymphocytes affectedLymphocytes affected Bone marrow makes Bone marrow makes
too many lymphocytes too many lymphocytes that do not mature that do not mature correctlycorrectly– Crowding out of other Crowding out of other
normal blood cellsnormal blood cells
– Immature lymphocytes Immature lymphocytes do not fight infection do not fight infection properlyproperly
health.allrefer.com
Pre-B cell ALLPre-B cell ALL
Overproliferation of Overproliferation of pre-B cellspre-B cells
B cell = WBC that B cell = WBC that produces antibodiesproduces antibodies
Pre-B cell = early Pre-B cell = early stage B cellstage B cell
Biol 169 lecture notes, Spring 2004
E2AE2A
Transcription factorTranscription factor E2A binding detected at the promoters and E2A binding detected at the promoters and
enhancers of several essential B-lineage enhancers of several essential B-lineage genesgenes– VpreB light chain promoterVpreB light chain promoter– EBF promoterEBF promoter– Mb-1 promoterMb-1 promoter
E2A Binds to DNAE2A Binds to DNA
E2A binds to DNA as a homodimeric complexE2A binds to DNA as a homodimeric complex
Aspland et al.
E2A is a bHLH proteinE2A is a bHLH protein
bHLH = basic helix-bHLH = basic helix-loop-helixloop-helix
Cooper et al.
The Normal Function of E2AThe Normal Function of E2A
Role in directing B Role in directing B cell lineage cell lineage commitmentcommitment
Also plays multiple Also plays multiple roles at later stages of roles at later stages of B cell development B cell development and maturationand maturation
Schebesta et al.
E2A Deficient MiceE2A Deficient Mice
Heterozygous embryos contain ~ ½ as many B cells as wildtype Heterozygous embryos contain ~ ½ as many B cells as wildtype embryosembryos
Homozygous mutant miceHomozygous mutant mice– Develop full term w/o apparent abnormalitiesDevelop full term w/o apparent abnormalities– High rate of postnatal deathHigh rate of postnatal death– Retarded postnatal growthRetarded postnatal growth– Contain no B cellsContain no B cells
http://compdiag.molgen.mpg.de/docs/
The Fusion of E2A with PBX1The Fusion of E2A with PBX1
t(1;19) translocationt(1;19) translocation Detected in ~23% of all pediatric pre-B cell Detected in ~23% of all pediatric pre-B cell
ALL casesALL cases Activation domains of E2A + Activation domains of E2A +
homeodomain (HD) regions of PBX1homeodomain (HD) regions of PBX1
The TranslocationThe Translocation
Aspland et al.
The Fusion has 2 Primary EffectsThe Fusion has 2 Primary Effects
Disrupts one allele of both E2A and PBX1Disrupts one allele of both E2A and PBX1– Reduction in levels of wildtype E2AReduction in levels of wildtype E2A
Generation of novel fusion gene, E2A-Generation of novel fusion gene, E2A-PBX1, expressed under the control of E2A PBX1, expressed under the control of E2A regulatory sequencesregulatory sequences
What does the fusion gene do?What does the fusion gene do?
Association of Hox Association of Hox proteins with E2A-proteins with E2A-PBX1 activates PBX1 activates transcription of many transcription of many Hox/PBX1 target Hox/PBX1 target genesgenes
Aspland et al.
The TargetsThe Targets
There are several targetsThere are several targets Wnt16Wnt16
– Encodes a growth factorEncodes a growth factor
– Normally expressed in Normally expressed in spleen, appendix, and spleen, appendix, and lymph nodeslymph nodes
– High levels expressed in High levels expressed in bone marrow of pre-B cell bone marrow of pre-B cell ALL patients carrying E2A-ALL patients carrying E2A-PBX1 hybrid genePBX1 hybrid gene
McWhirter et al.
E2A-PBX1 Constitutively E2A-PBX1 Constitutively Activates Wnt16Activates Wnt16
Members of PBX1 family normally repress Members of PBX1 family normally repress Wnt16 transcription in pre-B lymphocytesWnt16 transcription in pre-B lymphocytes
Fusion of E2A with PBX1 activates Wnt16Fusion of E2A with PBX1 activates Wnt16– Aberrant proliferation and/or survival of pre-B Aberrant proliferation and/or survival of pre-B
lineage cellslineage cells
Secondary MutationsSecondary Mutations
Pim1 and Notch1Pim1 and Notch1 Mice engineered to Mice engineered to
express:express:– E2A-PBX1 and either E2A-PBX1 and either
mutated Pim1 or mutated Pim1 or Notch1Notch1
– E2A-PBX1 aloneE2A-PBX1 alone