Induced GnasR201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling

Fibrous dysplasia (FD; Online Mendelian Inheritance in Man no. 174800) is a crippling skeletal disease caused by activating mutations of the GNAS gene, which encodes the stimulatory G protein Gαs. FD can lead to severe adverse conditions such as bone deformity, fracture, and severe pain, leading to functional impairment and wheelchair confinement. So far there is no cure, as the underlying molecular and cellular mechanisms remain largely unknown and the lack of appropriate animal models has severely hampered FD research. Here we have investigated the cellular and molecular mechanisms underlying FD and tested its potential treatment by establishing a mouse model in which the human FD mutation (R201H) has been conditionally knocked into the corresponding mouse Gnas locus. We found that the germ-line FD mutant was embryonic lethal, and Cre-induced Gnas FD mutant expression in early osteochondral progenitors, osteoblast cells, or bone marrow stromal cells (BMSCs) recapitulated FD features. In addition, mosaic expression of FD mutant Gαs in BMSCs induced bone marrow fibrosis both cell autonomously and non-cell autonomously. Furthermore, Wnt/β-catenin signaling was up-regulated in FD mutant mouse bone and BMSCs undergoing osteogenic differentiation, as we have found in FD human tissue previously. Reduction of Wnt/β-catenin signaling by removing one Lrp6 copy in an FD mutant line significantly rescued the phenotypes. We demonstrate that induced expression of the FD Gαs mutant from the mouse endogenous Gnas locus exhibits human FD phenotypes in vivo, and that inhibitors of Wnt/β-catenin signaling may be repurposed for treating FD and other bone diseases caused by Gαs activation.

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Bioimaging of Vascular Microenvironment Reveals Presence of Fli1a, Not VEGFR2, in Acute Lymphoblastic Leukemia Model in Syngeneic Zebrafish

Blood ◽

10.1182/blood.v118.21.2551.2551 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2551-2551

Author(s):

Sergei Revskoy ◽

Igor Mizgirev ◽

Seth J. Corey

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Large Scale ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cellular Mechanisms ◽

Bone Marrow Biopsies ◽

Response To Chemotherapy

Abstract Abstract 2551 Despite great advances in the curability of children with acute lymphoblastic leukemia (ALL), outcomes for pediatric and adult patients with relapsed ALL remain poor. This highlights the need for new approaches to ALL treatment and novel tools for screening of potential therapeutics. Dysregulated angiogenesis has been implicated both in the pathogenesis of leukemia and development of chemoresistance. However, the complexity of the bone marrow microenvironment and the precise contributions by the various components cannot be easily dissected in cell lines, tissue blocks, or mouse models. For instance, leukemia-associated angiogenesis was mainly characterized by immunostaining of bone marrow biopsies. High resolution in vivo bioimaging of fluorescence-tagged tumors and their microenvironment has recently become feasible due to establishment of transplantable tumor models in clonal syngeneic zebrafish. We have applied this model to dissection of cellular mechanisms of angiogenesis during stages of progression of T-ALL, This novel animal model enables us to 1) track leukemic cell proliferation and dissemination in vivo in different temperio-spatial and vascular contexts, and 2) follow up on cellular angiogenic events in response to leukemia progression including those occurring in response to chemotherapy for leukemia. In zebrafish, angiogenesis is similar to that of mammals and has been well characterized by using VEGFR2 and Fli1a transgenic reporter systems. In embryos, the fli1a:EGFP expression pattern mirrors that of VEGFR2 fluorescence in vascular endothelial cells. However, later in the development, in larvae and adult fish, the pattern of Fli1a or VEGFR2 expression diverges. This divergence further extends to angiogenesis in areas adjacent to T-ALL with more prominent development of Fli1a vasculature. Leukemic patches are characterized by a microenvironment where Fli1a is predominant and VEGFR2 is absent. We are now using cyclophosphamide treatment of leukemic fish to dissect the role of microenvironment and whether angiogenic factors are modified. These data yield new insights into molecular mechanisms of leukemogenesis in conjunction with angiogenesis. Furthermore, our findings would have predicted the lack of efficacy of VEGFR inhibitors in leukemia therapy. Our model offers an advantage for cost-efficient in vivo large scale screening system for antiangiogenic drugs for acute leukemia. Disclosures: No relevant conflicts of interest to declare.

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Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis

Cell Death and Disease ◽

10.1038/s41419-021-03877-4 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Chao Liu ◽

An-Song Liu ◽

Da Zhong ◽

Cheng-Gong Wang ◽

Mi Yu ◽

...

Keyword(s):

Bone Marrow ◽

Bone Formation ◽

Osteogenic Differentiation ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Regulatory System ◽

Circular Rna ◽

Luciferase Reporter ◽

Integrin Αv

AbstractBone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

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Molecular mechanisms of olfactory detection in insects: beyond receptors

Open Biology ◽

10.1098/rsob.200252 ◽

2020 ◽

Vol 10 (10) ◽

pp. 200252

Author(s):

Hayden R. Schmidt ◽

Richard Benton

Keyword(s):

Molecular Mechanisms ◽

Olfactory Receptors ◽

Environmental Chemicals ◽

Ecological Niches ◽

Cellular Mechanisms ◽

Signalling Molecules ◽

Olfactory Systems ◽

Lymph Fluid ◽

And Function

Insects thrive in diverse ecological niches in large part because of their highly sophisticated olfactory systems. Over the last two decades, a major focus in the study of insect olfaction has been on the role of olfactory receptors in mediating neuronal responses to environmental chemicals. In vivo , these receptors operate in specialized structures, called sensilla, which comprise neurons and non-neuronal support cells, extracellular lymph fluid and a precisely shaped cuticle. While sensilla are inherent to odour sensing in insects, we are only just beginning to understand their construction and function. Here, we review recent work that illuminates how odour-evoked neuronal activity is impacted by sensillar morphology, lymph fluid biochemistry, accessory signalling molecules in neurons and the physiological crosstalk between sensillar cells. These advances reveal multi-layered molecular and cellular mechanisms that determine the selectivity, sensitivity and dynamic modulation of odour-evoked responses in insects.

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Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Loss via Regulation of Akt/GSK3β/PTEN/NFATc1 Signaling Pathway and Calcineurin Activity

Marine Drugs ◽

10.3390/md17060345 ◽

2019 ◽

Vol 17 (6) ◽

pp. 345 ◽

Cited By ~ 5

Author(s):

Sheng-Hua Lu ◽

Yi-Jan Hsia ◽

Kuang-Chung Shih ◽

Tz-Chong Chou

Keyword(s):

Bone Loss ◽

Molecular Mechanisms ◽

Bone Erosion ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Nuclear Factor ◽

Activated T Cells ◽

Calcineurin Activity

Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.

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The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20153639 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3639 ◽

Cited By ~ 1

Author(s):

Giorgia Maroni ◽

Daniele Panetta ◽

Raffaele Luongo ◽

Indira Krishnan ◽

Federica La Rosa ◽

...

Keyword(s):

Bone Marrow ◽

Cell Fate ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Molecular Mechanisms ◽

Gene Dosage ◽

Homeobox Gene ◽

Fate Decision

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a “browning” effect in all fat tissues.

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Maintenance of hemopoietic stem cells and production of differentiated progeny in allogeneic and semiallogeneic bone marrow chimeras in vitro.

Journal of Experimental Medicine ◽

10.1084/jem.145.6.1612 ◽

1977 ◽

Vol 145 (6) ◽

pp. 1612-1616 ◽

Cited By ~ 86

Author(s):

T M Dexter ◽

M A Moore ◽

A P Sheridan

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Culture System ◽

Adherent Cells ◽

Cellular Mechanisms ◽

Graft Versus Host ◽

Proliferation And Differentiation ◽

Bone Marrow Chimeras

A culture system is described in which bone marrow-derived adherent cells can support prolonged proliferation and differentiation of genetically incompatible stem cells and precursor cells. The results suggest that the reactive cells responsible in vivo for host transplantation resistance and for graft-versus-host disease are selectively lost or inhibited in such cultures, which may provide a vehicle for studying some of the cellular mechanisms involved in transplantation resistance.

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FLT3-Targeted Therapy Selectively Kills MLL-Rearranged Infant and Childhood ALL Blasts In Vitro and in Vivo.

Blood ◽

10.1182/blood.v104.11.686.686 ◽

2004 ◽

Vol 104 (11) ◽

pp. 686-686 ◽

Cited By ~ 2

Author(s):

Patrick Brown ◽

Obdulio Piloto ◽

Mark Levis ◽

Sheila Shurtleff ◽

Dario Campana ◽

...

Keyword(s):

Bone Marrow ◽

Targeted Therapy ◽

Cell Lines ◽

Gene Rearrangements ◽

Human Leukemia ◽

Childhood All ◽

Activating Mutations ◽

Mll Gene ◽

Flt3 Expression

Abstract The FLT3 receptor tyrosine kinase has been convincingly implicated in the pathogenesis of human leukemia. In childhood acute lymphoblastic leukemia (ALL), FLT3 is expressed in 94% of B-lineage disease and 32% of T-lineage disease. Co-expression of FLT3 ligand (FL) may frequently occur in these cases, as we have observed constitutive activation of the wild type receptor in cell lines and primary samples. A smaller percentage of ALL cases harbor activating mutations of FLT3. Cases of ALL with MLL gene rearrangements are common among infants less than 1 year of age, and have a distinctly poor prognosis, with overall survival rates of approximately 20%. Gene expression studies have revealed that these cases express the highest levels of FLT3, and activating mutations of FLT3 also occur in 18% of MLL-rearranged ALL. We hypothesized that inhibition of FLT3 signaling would be selectively cytotoxic to ALL blasts with high levels of FLT3 expression, particularly if MLL rearrangements were present. We determined the anti-leukemic activity of CEP-701, a potent (IC50=3 nM) and selective small molecule FLT3 inhibitor, in 36 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. FLT3 expression level was determined by RNA microarray analysis or by FLT3 immunoprecipitation and immunoblotting, and FLT3 mutation status was determined by PCR analysis. MTT cytotoxicity assays and annexin V binding apoptosis assays were performed on all samples. CEP-701 induced more pronounced cytotoxicity at all six dose levels (5–100 nM) in samples that expressed high levels of FLT3 (N=23) compared to samples with low levels of expression (N=13). At 50 nM, for example, the MTT mean optical density was 45% that of untreated control in the FLT3 high group vs. 84% in the FLT3 low group (P<0.0001). Cytotoxicity was particularly pronounced in samples with MLL gene rearrangements (N=11, P=0.0006). Seven samples (five with MLL rearrangements) that were sensitive to CEP-701, and six samples that were resistant (none with MLL rearrangements), were examined by FLT3 immunoprecipitation and immunoblotting. All seven sensitive samples demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701. Conversely, 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. To assess the in vivo activity of FLT3-targeted therapy for MLL-rearranged ALL, six week old NOD/SCID mice were injected with MLL-rearranged primary infant leukemia blasts. Mice were treated with vehicle control, CEP-701 or EB10 (a fully humanized anti-FLT3 monoclonal antibody) for 14 weeks. Bone marrow was then harvested and assessed for engraftment of human cells. Inhibition of engraftment was achieved in the CEP-701-treated mice (mean engraftment 45%, N=5) and EB10-treated mice (mean engraftment 28%, N=4) compared to vehicle controls (mean engraftment 96%, N=9). Finally, in cytotoxicity and apoptosis assays utilizing MLL-rearranged cell lines and primary blast samples, schedule-dependent synergy between CEP-701 and several chemotherapy agents active in ALL was demonstrable, including doxorubicin, dexamethasone, l-asparaginase, etoposide, vincristine and cytarabine. We conclude that FLT3-targeted therapy is a promising novel approach to the treatment of MLL-rearranged ALL, a disease with dismal prognosis with current treatment approaches. Clinical testing is warranted.

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CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf–mediated interactions with bone marrow stromal cells

Blood ◽

10.1182/blood-2008-10-183772 ◽

2009 ◽

Vol 113 (18) ◽

pp. 4309-4318 ◽

Cited By ~ 41

Author(s):

Yu-Tzu Tai ◽

Ender Soydan ◽

Weihua Song ◽

Mariateresa Fulciniti ◽

Kihyun Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Molecular Mechanisms ◽

Myeloma Cell ◽

Marrow Stromal Cells ◽

Growth And Survival ◽

Multiple Myeloma Cell

Abstract CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient sera and correlates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNA decreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf–targeted cyclin D2-dependent proliferation, -integrin β7/αE-mediated myeloma adhesion to BMSCs, and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

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Genetic profiling of human bone marrow and adipose tissue-derived mesenchymal stem cells reveals differences in osteogenic signaling mediated by graphene

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01024-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Amber F. MacDonald ◽

Ruby D. Trotter ◽

Christopher D. Griffin ◽

Austin J. Bow ◽

Steven D. Newby ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Cellular Adhesion ◽

Bone Diseases ◽

Low Oxygen ◽

Gene Expressions ◽

Time Point

Abstract Background In the last decade, graphene surfaces have consistently supported osteoblast development of stem cells, holding promise as a therapeutic implant for degenerative bone diseases. However, until now no study has specifically examined the genetic changes when stem cells undergo osteogenic differentiation on graphene. Results In this study, we provide a detailed overview of gene expressions when human mesenchymal stem cells (MSCs) derived from either adipose tissue (AD-MSCs) or bone marrow (BM-MSCs), are cultured on graphene. Genetic expressions were measured using osteogenic RT2 profiler PCR arrays and compared either over time (7 or 21 days) or between each cell source at each time point. Genes were categorized as either transcriptional regulation, osteoblast-related, extracellular matrix, cellular adhesion, BMP and SMAD signaling, growth factors, or angiogenic factors. Results showed that both MSC sources cultured on low oxygen graphene surfaces achieved osteogenesis by 21 days and expressed specific osteoblast markers. However, each MSC source cultured on graphene did have genetically different responses. When compared between each other, we found that genes of BM-MSCs were robustly expressed, and more noticeable after 7 days of culturing, suggesting BM-MSCs initiate osteogenesis at an earlier time point than AD-MSCs on graphene. Additionally, we found upregulated angiogenic markers in both MSCs sources, suggesting graphene could simultaneously attract the ingrowth of blood vessels in vivo. Finally, we identified several novel targets, including distal-less homeobox 5 (DLX5) and phosphate-regulating endopeptidase homolog, X-linked (PHEX). Conclusions Overall, this study shows that graphene genetically supports differentiation of both AD-MSCs and BM-MSCs but may involve different signaling mechanisms to achieve osteogenesis. Data further demonstrates the lack of aberrant signaling due to cell-graphene interaction, strengthening the application of specific form and concentration of graphene nanoparticles in bone tissue engineering. Graphic abstract

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Mice with AML1 (Runx1) Haploinsufficiency Have Significant Platelet Abnormalities That Accurately Mimic Those Seen in Human Patients with Germ Line Inactivating Mutations in AML1.

Blood ◽

10.1182/blood.v104.11.1595.1595 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1595-1595

Author(s):

Weili Sun ◽

Shirley Steward ◽

Tamara Pestina ◽

Carl W. Jackson ◽

James R. Downing

Keyword(s):

Acute Leukemia ◽

Platelet Function ◽

Molecular Mechanisms ◽

Germ Line ◽

Genetic Alterations ◽

Loss Of Function ◽

Hematopoietic Stem ◽

Transcriptional Targets ◽

Platelet Disorder

Abstract The AML1/CBFβ transcription complex, a critical regulator of the formation of definitive hematopoietic stem cells (HSC), is one of the most frequent targets of genetic alterations in acute leukemia. In addition to somatic alterations of AML1 and CBFβ in acute leukemia, germ-line loss-of-function mutations of AML1 are the underlying cause of an autosomal dominant familial platelet disorder with a predisposition to acute myeloid leukemia (FPD/AML). Importantly, a subset of the mutations identified in families with FPD/AML result in AML1 null allele, suggesting that AML1 haploinsufficiency is the underlying molecular abnormality. To explore the functional consequences of AML1 halpoinsufficiency on megakaryocyte development and platelet function, we analyzed the hematopoietic system of AML1+/- mice. Loss of a single AML1 allele resulted in a 15% reduction in the number of circulating platelets and a significant impairment in platelet function including a decrease in dense granule content and an impaired ability to aggregate in response to collagen stimulation. Further analysis indentified a left shift in the DNA ploidy of megakaryocytes and a reduction in GPV expression, consistent with impaired megakaryocyte maturation. In addition, electron microscopy indicated a reduction in platelet demarcation channels within the cytoplasm of megakaryocytes. Importantly, however, we did not observe a reduction in the total number of megakaryoctyes or a decrease in megakaryocyte colony forming units. These data suggest that the haploinsufficiency of AML1+/− does not alter the initial formation of megakaryocytes, but instead impairs the ability of these cells to efficiently mature and produce functional platelets. To explore the underlying mechanism responsible for the observed impairment in megakaryocyte maturation, we analyzed the pattern of expression of several putative AML1 transcriptional targets. Although AML1 binding sites have been identified within the promoter of c-mpl, the gene encoding the receptor for thrombopoietin (TPO), we did not observe any difference in c-mpl expression levels or in circulating TPO concentration between AML1+/− and +/+ mice. In addition, in vivo TPO stimulation induced a similar magnitude of megakaryocyte maturation and platelet production in both AML1+/+ and +/− mice. By contrast, analysis of members of the protein kinase C (PKC) family of gene, several which have been identified as transcriptional targets of AML1, revealed a reduction in PKCδ levels in platelets from AML1+/− mice. Taken together, our data suggest that AML1 haploinsufficiency leads to abnormalities in platelet that are identical to those observed in patients with FPD/AML. Thus, these mice should prove useful for exploring the molecular mechanisms through which AML regulates the normal maturation of megakaryocytes. Our early analysis suggests altered PKCδ signaling is a possible contributing factor to the observed phenotypic abnormalities.

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