Overexpression of HOXB3 in Hematopoietic Cells Causes Defective Lymphoid Development and Progressive Myeloproliferation

Sauvageau, Guy; Þorsteinsdóttir, Unnur; Hough, Margaret R.; Hugo, Patrice; Helson, Lawrence; Largman, Corey; Humphries, R. Keith

doi:10.1016/s1074-7613(00)80238-1

Cited by 169 publications

(125 citation statements)

References 40 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…Pbx1 possesses a divergent homeodomain DNA binding motif and appears to function in collaboration with other homeodomain containing proteins as part of large nucleoprotein complexes (Berthelsen et al, 1998;Goudet et al, 1999;Jacobs et al, 1999;Shen et al, 1999). Normal regulation of the proteins involved in these complexes is essential for both normal embryonic development Veraksa et al, 2000;Capecchi, 1997) and the establishment and maintenance of definitive hematopoiesis (Sauvageau et al, 1995(Sauvageau et al, , 1997Lawrence et al, 1996;Fuller et al, 1999;Buske et al, 2001;Thorsteinsdottir et al, 2001;DiMartino et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of multiple domains involved in the subcellular localization of the hematopoietic Pbx interacting protein (HPIP)

et al. 2002

View full text Add to dashboard Cite

We have previously reported the cloning of the Hematopoietic Pbx Interacting Protein (HPIP), a novel protein discovered through its interaction with Pbx1. HPIP is expressed in early hematopoietic precursors, can bind all members of the Pbx family and can inhibit the transcriptional activation of the oncogene E2A-Pbx. To further understand the function of HPIP, we have analysed its cellular localization and characterized its functional localization domains. Using fluorescence microscopy to follow the distribution of different HPIP sequences fused to GFP, we found that HPIP localizes predominantly to cytoskeletal fibers but has the potential ability to shuttle between the nucleus and the cytosol. The cytoskeletal localization of HPIP is mediated by an N-terminal leucine rich region (between aa 190 -218) and can be disrupted by the microtubule destabilizing drug vincristine. The HPIP C-terminal domain (aa 443 -731) bears a nuclear export activity that is blocked by the CRM1 inhibitor Leptomycin B. In addition, we found two basic amino acid regions located between aa 485 -505 and aa 695 -720 that contain nuclear import activities attenuated by nuclear export. These observations support a model in which the constitutive attachment of HPIP to the cytoskeleton could be modified by changes in functional domains implicated in nuclear export, import and cytoskeleton binding sequences, allowing the molecule to shuttle between the nucleus and the cytosol.

show abstract

Section: Introductionmentioning

confidence: 99%

Functional characterization of multiple domains involved in the subcellular localization of the hematopoietic Pbx interacting protein (HPIP)

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Retroviral infection of Hoxb-8 into murine bone marrow cells results in leukemia after transplantation into irradiated hosts [12]. Subsequently, it has been shown that pathological aberrations in the hematopoietic system can be caused by deregulated expression of a number of homeobox genes, including HOXA10 [13], HOXB3 [14], and HOXB4 [15]. However, these experiments do not address the question of whether Hox genes are required for normal hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the homeobox gene Hoxb-6 in mice results in increased numbers of early erythrocyte progenitors

Kappen

2000

Am. J. Hematol.

View full text Add to dashboard Cite

Hox genes encode transcription factors that are required for proper development of certain tissues and for patterning of the hindbrain, the limbs, and skeleton. They are also expressed in the hematopoietic system with a preference for specific cell lineages. To determine the role of Hoxb-6 in normal hematopoiesis, mice with a targeted disruption in the Hoxb-6 gene were generated. Mature hematopoietic cell types and immune responses are normal in homozygous Hoxb-6 mutants. Clonogenic progenitor cell assays demonstrate an increased number of early erythroid progenitor cells in the bone marrow and fetal liver of mutants, while differentiation of other cell lineages is unaffected. These results suggest that Hoxb-6 controls the generation, proliferation, or survival of erythroid progenitor cells. Am.

show abstract

“…8 On the other hand, up-regulation of HOXB3 expression perturbed both T and B lymphoid development and myelopoiesis leading to a myeloproliferative disorder in mice. 9 Analysis of samples directly isolated from patients with leukemia has suggested a role for HOX genes and their cofactors in malignant hematopoiesis. In AML associated with the chromosomal rearrangement t(7;11)(p15;p15) HOXA9 is fused to nucleoporin NUP98.…”

Section: Introductionmentioning

confidence: 99%

True

1999

Leukemia

View full text Add to dashboard Cite

To explore the possibility that deregulated HOX gene expression might commonly occur during leukemic hematopoiesis, we compared the relative levels of expression of these and related genes in phenotypically and functionally defined subpopulations of AML blasts and normal hematopoietic cells. Initially, a semi-quantitative RT-PCR technique was used to amplify total cDNA from total leukemic blast cell populations from 20 AML patients and light density cells from four normal bone marrows. Expression of HOX genes (A9, A10, B3 and B4), MEIS1 and MLL was easily detected in the majority of AML samples with the exception of two samples from patients with AML subtype M3 (which expressed only MLL). Low levels of HOXA9 and A10 but not B3 or B4 were seen in normal marrow while MLL was easily detected. PBX1a was difficult to detect in any AML sample but was seen in three of four normal marrows. Cells from nine AML patients and five normal bone marrows were FACS-sorted into CD34 ؉ CD38 ؊ , CD34 ؉ CD38 ؉ and CD34 ؊ subpopulations, analyzed for their functional properties in long-term culture (LTC) and colony assays, and for gene expression using RT-PCR. 93 ؎ 14% of AML LTC-initiating cells, 92 ± 14% AML colony-forming cells, and Ͼ99% of normal LTC-IC and CFC were CD34 ؉ . The relative level of expression of the four HOX genes in amplified cDNA from CD34 ؊ as compared to CD34 ؉ CD38 ؊ normal cells was reduced Ͼ10-fold. However, in AML samples this down-regulation in HOX expression in CD34 ؊ as compared to CD34 ؉ CD38 ؊ cells was not seen (P Ͻ 0.05 for comparison between AML and normal). A similar difference between normal and AML subpopulations was seen when the relative levels of expression of MEIS1, and to a lesser extent MLL, were compared in CD34 ؉ and CD34 ؊ cells (P Ͻ 0.05). In contrast, while some evidence of down-regulation of PBX1a was found in comparing CD34 ؊ to CD34 ؉ normal cells it was difficult to detect expression of this gene in any subpopulation from most AML samples. Thus, the down-regulation of HOX, MEIS1 and to some extent MLL which occurs with normal hematopoietic differentiation is not seen in AML cells with similar functional and phenotypic properties.

show abstract

Overexpression of HOXB3 in Hematopoietic Cells Causes Defective Lymphoid Development and Progressive Myeloproliferation

Cited by 169 publications

References 40 publications

Functional characterization of multiple domains involved in the subcellular localization of the hematopoietic Pbx interacting protein (HPIP)

Functional characterization of multiple domains involved in the subcellular localization of the hematopoietic Pbx interacting protein (HPIP)

Disruption of the homeobox gene Hoxb-6 in mice results in increased numbers of early erythrocyte progenitors

True

Contact Info

Product

Resources

About