Commonly dysregulated genes in murine APL cells

Yuan, Wenlin; Payton, Jacqueline E.; Holt, Matthew; Link, Daniel C.; Watson, Mark A.; DiPersio, John F.; Ley, Timothy J.

doi:10.1182/blood-2006-07-036640

Cited by 34 publications

(34 citation statements)

References 54 publications

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“…In brief, bone marrow aspirates were obtained from patients that gave informed consent. RNA was prepared from the unfractionated snap-frozen cell pellets and profiled using the Affymetrix Human Genome U133 Plus 2.0 Array GeneChip microarrays (Affymetrix) at the Siteman Cancer Center Molecular and Genomic Analysis Core Facility (38).…”

Section: Methodsmentioning

confidence: 99%

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

Welch¹,

Yuan²,

Ley³

2011

J. Clin. Invest.

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Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that generates the fusion protein promyelocytic leukemia-retinoic acid receptor α (PML-RARA) in nearly all cases. Multiple prior mouse models of APL constitutively express PML-RARA from a variety of non-Pml loci. Typically, all animals develop a myeloproliferative disease, followed by leukemia in a subset of animals after a long latent period. In contrast, human APL is not associated with an antecedent stage of myeloproliferation. To address this discrepancy, we have generated a system whereby PML-RARA expression is somatically acquired from the mouse Pml locus in the context of Pml haploinsufficiency. We found that physiologic PML-RARA expression was sufficient to direct a hematopoietic progenitor self-renewal program in vitro and in vivo. However, this expansion was not associated with evidence of myeloproliferation, more accurately reflecting the clinical presentation of human APL. Thus, at physiologic doses, PML-RARA primarily acts to increase hematopoietic progenitor self-renewal, expanding a population of cells that are susceptible to acquiring secondary mutations that cause progression to leukemia. This mouse model provides a platform for more accurately dissecting the early events in APL pathogenesis. IntroductionMore than 95% of acute promyelocytic leukemia (APL; FAB-M3) cases are associated with the recurrent t(15;17)(q22:q11) translocation, which results in the expression of a fusion transcript promyelocytic leukemia-retinoic acid receptor α (PML-RARA), inconsistent expression of a reciprocal fusion product (RARA-PML), and haploinsufficiency for both PML and RARA (1, 2). Although APL has served as an important model disease for understanding leukemogenic pathways directed by a specific translocation, the precise mechanisms by which t(15;17) initiates leukemia remain unknown.Several mouse models have been used to study the mechanisms by which PML-RARA causes transformation (reviewed in refs. 3, 4). These models have used viral transduction, transgenic, and knockin strategies; regulatory sequences from the MRP8 gene (also known as S100 calcium binding protein A8 [S100A8]) and human and murine cathepsin G (CTSG and Ctsg, respectively) genes have been used to direct the expression of PML-RARA to the myeloid compartment (5-8), where can cause a myeloproliferative disease and APL after a long latent period.However, there are many issues with existing mouse models of APL that must be addressed to fully understand how PML-RARA works. (a) The dose of PML-RARA is known to be important for AML penetrance, but no model to our knowledge has yet expressed PML-RARA from the endogenous Pml locus. This has not previously been attempted, since Pml is ubiquitously expressed, and since widespread expression of PML-RARA during development causes embryonic lethality (9, 10). (b) t(15;17) is a somatically acquired event, but all prior models have used constitutive PML-RARA expression, raising the possibility that hematopoietic cells may have a...

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Section: Methodsmentioning

confidence: 99%

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

Welch¹,

Yuan²,

Ley³

2011

J. Clin. Invest.

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“…22 We previously reported that leukemic blasts can be identified by the abnormal coexpression of the myeloid surface antigen Gr-1 and the early hematopoietic marker CD34 ( Figure 1A). 22,27,28 These Gr-1 ϩ CD34 ϩ APL cells partially retain the ability to terminally differentiate toward mature granulocytes and can be adoptively transferred to secondary recipients, which develop an identical, rapidly fatal leukemia within 2 to 3 weeks (dose and tumor dependent) after tumor inoculation. 22,[27][28][29] Finally, as shown in Figure 1A, Gr-1 ϩ CD34 ϩ blast cells express cell-surface CXCR4, with increased expression observed on cells obtained from the peripheral blood compared with the spleen and bone marrow.…”

Section: In Vivo Bioluminescence Imaging Of Aml Cell Traffickingmentioning

confidence: 99%

“…Of note, since Gr-1 ϩ CD34 ϩ APL cells partially retain the ability to terminally differentiate toward mature granulocytes, the majority of circulating baseline and mobilized cells in the leukemic mice shown in Figure 3C through E are mature granulocytes derived from the APL blast population. 22,27,28 We next evaluated whether repetitive daily injections of AMD3100 could remobilize normal hematopoietic progenitors and APL cells into the circulation. In these studies, B6129F1 mice were injected with 10 6 mCG PR/ϩ APL cells and administered a single dose of AMD3100 for 5 consecutive days 12 days after mCG PR/ϩ APL injection.…”

Section: Mobilization Of Apl Blasts By Amd3100mentioning

confidence: 99%

Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100

Nervi¹,

Ramírez²,

Rettig³

et al. 2009

Blood

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The CXCR4-SDF-1 axis plays a central role in the trafficking and retention of normal and malignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acute promyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, to examine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murine cathepsin G-PML-RAR␣ knockin mouse were genetically modified with firefly luciferase (APL luc ) to allow tracking by bioluminescence imaging. Coculture of APL luc cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APL luc cells rapidly migrated to the BM followed by egress to the spleen then to the peripheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic mice induced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, which peak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plus AMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treated with chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the critical tethers that promote AMLniche interactions. (Blood. 2009;113: 6206-6214) IntroductionHematopoietic stem cells (HSCs) reside in the bone marrow (BM) and interact with a highly organized microenvironment composed of a diverse population of stromal cells and an extracellular matrix rich in fibronectin, collagens, and various proteoglycans. The interaction between HSCs and the BM microenvironment is critical in regulating HSC processes such as trafficking, self-renewal, proliferation, and differentiation.Egress (mobilization) of stem cells from the BM to the peripheral blood can be induced by cytokines (G-CSF and GM-CSF), chemokines (Gro-␤ and IL-8), or by small molecule inhibitors of both CXCR4 and VLA-4. 1 Interaction between the chemokine, SDF-1, and its cognate receptor CXCR4 functions as a key regulator of stem cell mobilization and trafficking. 2,3 Constitutive secretion of SDF-1 by marrow stromal cells creates a gradient by which HSCs expressing the receptor CXCR4 home to and interact with its marrow niche. 4 In response to factors such as G-CSF, SDF-1 production is down-regulated by stromal cells that release HSCs into the peripheral circulation. 5 AMD3100 is a bicyclam molecule that potently, selectively, and reversibly antagonizes the binding of SDF-1 to CXCR4. 6 In multiple clinical studies, AMD3100 rapidly and effectively mobilizes HSCs into the peripheral circulation and is currently under development as a stem cell mobilization agent prior to high-dose chemotherapy for multiple myeloma, non-Hodgkin lymphoma, and other hematologic malignancies. [7][8][9] In acute myeloid leukemia (AML), the bone marrow microenvironment provides the primary site of minimal residual disease after chemotherapy. [10][11][12] Similar to normal HSCs, AM...

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“…Affymetrix Expression Console software was used to process array images, export signal data, and evaluate image and data quality relative to standard Affymetrix quality-control metrics. 35 These data have been deposited into a public database (Gene Expression Omnibus: GSE23291).…”

Section: Expression Array Profilingmentioning

confidence: 99%

Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice

Welch¹,

Klco

Varghese

et al. 2011

Blood

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RARA (retinoic acid receptor alpha) haploinsufficiency is an invariable consequence of t(15;17)(q22;q21) translocations in acute promyelocytic leukemia (APL). Retinoids and RARA activity have been implicated in hematopoietic selfrenewal and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis, we crossed Rara ؉/؊ mice with mice expressing PML (promyelocytic leukemia)-RARA from the cathepsin G locus (mCG-PR). We found that Rara haploinsufficiency cooperated with PML-RARA, but only modestly influenced the preleukemic and leukemic phenotype. Bone marrow from mCG-PR ؉/؊ ؋ Rara ؉/؊ mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation, and increased competitive advantage after transplantation. Rara haploinsufficiency did not alter mCG-PR-dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; leukemia in mCG-PR ؉/؊ ؋ Rara ؉/؊ mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL cells from these mice were responsive to all-trans retinoic acid and had virtually no differences in expression profiling compared with tumors arising in mCG-PR ؉/؊ ؋ Rara ؉/؉ mice. These data show that Rara haploinsufficiency (like Pml haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis of APL in mice, but that PML-RARA is the t(15;17) disease-initiating mutation. (Blood. 2011;117(8):2460-2468)

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Commonly dysregulated genes in murine APL cells

Cited by 34 publications

References 54 publications

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100

Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice

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