The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver

DiMartino, Jorge; Selleri, Licia; Traver, David; Firpo, Meri T.; Rhee, Joon Whan; Warnke, Roger A.; O’Gorman, Stephen; Weissman, Irving L.; Cleary, Michael L.

doi:10.1182/blood.v98.3.618

Cited by 151 publications

(135 citation statements)

References 39 publications

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“…Consistent with their biochemical interactions, lack of Meis1 partially phenocopies Pbx1 deficiency in hematopoietic development (DiMartino et al 2001;Hisa et al 2004). In MLL leukemias, Meis1 contributions are dependent on the integrity of its Pbx dimerization motifs.…”

Section: Mll-mediated Transformation Is Dependent On Pbx Functionmentioning

confidence: 63%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

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259

273

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Oncogenic mutations of the MLL histone methyltransferase confer an unusual ability to transform non-self-renewing myeloid progenitors into leukemia stem cells (LSCs) by mechanisms that remain poorly defined. Misregulation of Hox genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of MLL leukemias, which are clinically heterogeneouspresumably reflecting differences in LSC biology and/or frequency. TALE (three-amino-acid loop extension) class homeodomain proteins of the Pbx and Meis families are also misexpressed in this context, and we thus employed knockout, knockdown, and dominant-negative genetic techniques to investigate the requirements and contributions of these factors in MLL oncoprotein-induced acute myeloid leukemia. Our studies show that induction and maintenance of MLL transformation requires Meis1 and is codependent on the redundant contributions of Pbx2 and Pbx3. Meis1 in particular serves a major role in establishing LSC potential, and determines LSC frequency by quantitatively regulating the extent of self-renewal, differentiation arrest, and cycling, as well as the rate of in vivo LSC generation from myeloid progenitors. Thus, TALE proteins are critical downstream effectors within an essential homeoprotein network that serves a rate-limiting regulatory role in MLL leukemogenesis.[Keywords: Leukemia stem cells; MLL; Meis1; Pbx; TALE homeodomain proteins] Supplemental material is available at http://www.genesdev.org.

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Section: Mll-mediated Transformation Is Dependent On Pbx Functionmentioning

confidence: 63%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

Self Cite

259

273

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“…Germline KOs of hematopoietic master regulators die at discrete points or within narrow windows of embryonic development, for example, GATA1 at E10.5 to E11.5, 48 PBX1 at E15 to E16, 49 EKLF at E15 to E16, 50 and SOX4 at E14, although SOX4 À/À embryos expire from failed cardiac development. 51 In contrast Fubp1 À/À embryonic lethality occurs across half of gestation, from E10.5 until birth, suggesting that FBP is supportive of, but not essential for, multiple hematopoietic stages and transitions.…”

Section: Discussionmentioning

confidence: 99%

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1 À/À ) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1 À/À hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1 À/À hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1 À/À embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. The transcription factor Myc plays a decisive role in cell growth, differentiation, and senescence and so must be highly regulated. The far upstream element (FUSE) binding protein (FBP) binds single-stranded DNA of FUSE 1.7 kb upstream of the major P2 promoter of the human MYC gene. 1e3 FUSE melting in response to dynamic supercoils propagated from the MYC promoters enables FBP binding. FBP activates TFIIH helicase activity to accelerate the transcription cycle from preinitiation complex assembly through promoter escape and onto pause release. 4e6 Positive regulation of MYC is at least in part counteracted by FBP interacting repressor (FIR) that binds FBP and FUSE and opposes TFIIH helicase activity, retarding the transcription cycle. 5,7 Besides MYC, FBP regulates the expression of the cyclin-dependent kinase inhibitor p21, stathmin, and USP29, a powerful stabilizer of p53 induced by oxidative stress. 8e10 Because the FBP/FIR system reads single-stranded DNA sequences exposed by transcriptionally generated dynamic supercoiling, it is proposed that the FBP/ FIR/FUSE system serves as a molecular cruise control that monitors the mechanical output of promoters in real time while providing both positive and negative feedback. 11e13Supported by the NIH

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“…Thus, loss-of-function mutations of Hox cofactors are predicted to disrupt multiple HOX-dependent pathways. Indeed, Pbx1 and Meis1 mutant animals are embryonic lethal and recapitulate the HSC defects observed in Hox knockout models, indicative of a role for these genes in HSC self-renewal/proliferation (DiMartino et al, 2001;Hisa et al, 2004).…”

Section: Deficiencies Of Hox Regulators Demonstrate a Role For Hox Gementioning

confidence: 91%

Hox genes in hematopoiesis and leukemogenesis

2007

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The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver

Cited by 151 publications

References 39 publications

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Hox genes in hematopoiesis and leukemogenesis

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