Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.

Perkins, Andrew C.; Kongsuwan, Kritaya; Visvader, Jane E.; Adams, Jerry M.; Cory, Suzanne

doi:10.1073/pnas.87.21.8398

Cited by 144 publications

(101 citation statements)

References 33 publications

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“…Much of this evidence comes from surveys that demonstrate increased expression of HOX genes and/or their regulators in a broad range of solid tumors (Celetti et al, 1993;Cillo, 1994) and leukemias (Look, 1997). In addition, overexpression of several HOX genes leads to either expansion of particular hematopoietic compartments Crooks et al, 1999) or to overt cellular transformation (Perkins et al, 1990;Thorsteinsdottir et al, 1997;Kroon et al, 1998). Several previous studies showed that enforced expression of the HOXB4 protein resulted in hyperproliferation.…”

Section: Introductionmentioning

confidence: 99%

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Kömüves

Michael

Arbeit

et al. 2002

Developmental Dynamics

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The HOX homeodomain proteins are fundamental regulators of organ and tissue development, where they are thought to function as transcription factors, and HOX gene expression has been associated with numerous types of cancers. Previous studies have demonstrated that enforced expression of the HOXB4 protein transforms cultured fibroblasts and leads to a selective expansion of the hematopoietic stem cell pool, suggesting that this protein might play a role in cellular proliferation. In support of this concept, we now show that enforced expression of HOXB4 in human neonatal keratinocytes results in increased cellular proliferation and colony formation as well as decreased expression of the alpha-2-integrin and CD44 cell surface adhesion molecules. We previously have reported HOXB4 gene expression in the basal and suprabasal layers of developing human skin and now show extensive HOXB4 mRNA in psoriatic skin and basal cell carcinoma. In fetal human skin HOXB4 protein expression was both nuclear and cytoplasmic within epidermal basal cells and in hair follicle inner and outer root sheath cells, whereas strong nuclear signals were observed in the bulge region. In adult skin, HOXB4 protein expression was both nuclear and cytoplasmic, but was predominantly localized to the intermediate and differentiated cell layers. In contrast to the striking gradient patterns of HOX gene and protein expression previously described in developing spinal cord and limb, HOXB4 protein was uniformly detected in all regions of the fetal and adult skin. Although little HOXB4 signal localized to proliferative cell layers, as marked by proliferating cell nuclear antigen (PCNA) staining, in normal adult epidermis, nuclear HOXB4 protein expression substantially overlapped with PCNA-positive cell in a series of samples of hyperproliferative skin. Taken together, these data suggest that nuclear HOXB4 protein may play a role in the regulation of cellular proliferation/adhesion in developing fetal human epidermis and in hyperproliferation conditions, including cancers, in adult epidermis.Published 2002 Wiley-Liss, Inc. †

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Section: Introductionmentioning

confidence: 99%

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

Kömüves

Michael

Arbeit

et al. 2002

Developmental Dynamics

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“…Evidence for a functional role of Hox genes in the hematopoietic system was initially provided by the finding that Hoxb-8 is deregulated in myeloid leukemia cells [9,10] and that elevated Hoxb-8 expression leads to alterations in myeloid differentiation [11]. 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].…”

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.

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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.

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“…Perturbations in Hox gene expression pro®le have been associated with leukemic transformation. For example, the WEHI-3B leukemic cell line most likely originated from proviral insertional activation of Hoxb8 and interleukin-3 (IL-3) (Blatt et al, 1988), since retroviral over-expression of these two genes in murine bone marrow cells causes an aggressive polyclonal acute leukemia, whereas neither gene alone is acutely transforming (Perkins et al, 1990). Furthermore, a high proportion of mice transplanted with bone marrow cells over-expressing Hoxb8, or Hoxa10 or Hoxb3 eventually develop an acute myeloid leukemia after a latency period of several months (Perkins and Cory, 1993;Thorsteinsdottir et al, 1997;Sauvageau et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

et al. 1998

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The products of PBX homeobox genes, which were initially discovered in reciprocal translocations occurring in human leukemias, have been shown to cooperate in the in vitro DNA binding with HOX proteins. Despite the growing body of data implicating Hox genes in the development of various cancers, little is known about the role of HOX ± PBX interactions in the regulation of proliferation and induction of transformation of mammalian cells. We build on the existing model of Hoxinduced transformation of Rat-1 cells to show that both cellular transformation and proliferation induced by Hoxb4 and Hoxb3 are greatly modulated by the levels of available PBX1 present in these cells. Furthermore, we show that the transforming capacity of these two HOX proteins depends on their conserved tetrapeptide and homeodomain regions which mediate binding to PBX and DNA, respectively. Taken together, results of this study demonstrate that cooperation between HOX and PBX proteins modulates cellular proliferation and strongly suggest that cooperative DNA binding by these two groups of proteins represent the basis for Hoxinduced cellular transformation.

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Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.

Abstract: In the murine myelomonocytic leukemia WEHI-

Cited by 144 publications

References 33 publications

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation

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

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

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