PBX, MEIS/PREP, and HOX genes encode interacting transcription factors that regulate development. Their mutation produces oncogenes that cause human leukemia and other tumors. Pbx, Meis/Prep, and Hox proteins are also implicated as subordinate oncoproteins functionally required for leukemogenesis by other human oncogenes. Thus, understanding oncogenesis by individual Pbx, Meis/Prep or Hox oncogenes will yield a broader understanding of human leukemia in general. This proposal focuses on understanding how Pbx proteins control development and hematopoiesis (Aims 1 and 2) and how the human E2a-Pbxl oncogene causes AML and preB ALL (Aims 3 and 4). Health-relatedness: Just as understanding oncogenesis by signal transduction oncoproteins led to the development of therapeutic inhibitors of cell proliferation, so also understanding the biochemical mechanism of oncoproteins that block hematopoietic differentiation will establish a rational to generate drugs that inhibit their function and promote differentiation. Because oncogenes that promote proliferation and inhibit differentiation cooperate to cause leukemia, drugs that inhibit proliferation and promote differentiation should cooperate to cure leukemia.
Aim 1. Determine how Pbx homodimerization (in the absence of DNA) and Pbx:Meis/Prep heterodimerization regulate DNA-binding and nuclear import of Pbx proteins. Determine how Pbx proteins function as transcriptional coactivators.
Aim 2. Using knockout technology, determine the role of Pbx2 in mouse development in general, and in regulating lineage commitment, differentiation progression, and gene transcription during hematopoiesis in particular. Make conditional Pbx2/Pbxl, or Pbx2/Pbx3 mice to determine the effect of double knockouts on hematopoietic differentiation.
Aim 3 : Use conditional E2a-ER-Pbxl to determine how E2 about-Pbxl prevents transcription of myeloid differentiation genes, focusing, mechanistically, on MRP8. Determine whether direct E2a-Pbxl targets reestablish a differentiation block in conditionally-immortalized E2a-ER-Pbxl myeloblasts and are activated in human t(l;19) pre-B ALL (L-Myc is one such target).
Aim 4 : Establish the cellular impact of E2a-Pbxl in models of pre-B cell leukemia induced by coexpression of Ras6l L plus E2a-Pbxl, or in transgenic mice expressing wild-type or conditional E2a-ER-Pbxl genes driven by the early, hematopoietic specific, Vav promoter. Identify the biochemical domains of E2a-Pbxl required to cause pre-B ALL, and begin to identify a genetic mechanism by which E2a-ER-Pbxl causes pre-B cell ALL.
|Pasillas, Martina P; Shah, Meera; Kamps, Mark P (2011) NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome. Hum Mutat 32:292-8|
|Wang, Gang G; Cai, Ling; Pasillas, Martina P et al. (2007) NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9:804-12|
|Wang, Gang G; Pasillas, Martina P; Kamps, Mark P (2006) Persistent transactivation by meis1 replaces hox function in myeloid leukemogenesis models: evidence for co-occupancy of meis1-pbx and hox-pbx complexes on promoters of leukemia-associated genes. Mol Cell Biol 26:3902-16|
|Wang, Gang G; Calvo, Katherine R; Pasillas, Martina P et al. (2006) Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nat Methods 3:287-93|
|Wang, Gang G; Pasillas, Martina P; Kamps, Mark P (2005) Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus. Blood 106:254-64|
|Sykes, David B; Kamps, Mark P (2004) E2a/Pbx1 induces the rapid proliferation of stem cell factor-dependent murine pro-T cells that cause acute T-lymphoid or myeloid leukemias in mice. Mol Cell Biol 24:1256-69|
|Calvo, Katherine R; Sykes, David B; Pasillas, Martina P et al. (2002) Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene 21:4247-56|
|Calvo, K R; Knoepfler, P S; Sykes, D B et al. (2001) Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia. Proc Natl Acad Sci U S A 98:13120-5|
|Knoepfler, P S; Sykes, D B; Pasillas, M et al. (2001) HoxB8 requires its Pbx-interaction motif to block differentiation of primary myeloid progenitors and of most cell line models of myeloid differentiation. Oncogene 20:5440-8|
|Sykes, D B; Kamps, M P (2001) Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins. Blood 98:2308-18|
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