Instructor, Medicine - Hematology
Board Certification: American Board of Internal Medicine, Hematology (2019)
Fellowship: Stanford University Hematology and Oncology Fellowship (2018) CA
Board Certification: American Board of Internal Medicine, Internal Medicine (2014)
Residency: University of Utah Internal Medicine Residency (2014) UT
Medical Education: University of Utah School of Medicine Registrar (2011) UT
PhD, University of Utah School of Medicine, Cellular and Molecular Immunology (2007)
- Donor-derived acute promyelocytic leukemia presenting as myeloid sarcoma in a transplanted kidney. Leukemia 2020
IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia.
Science translational medicine
2020; 12 (538)
Most patients with acute myeloid leukemia (AML) die from complications arising from cytopenias resulting from bone marrow (BM) failure. The common presumption among physicians is that AML-induced BM failure is primarily due to overcrowding, yet BM failure is observed even with low burden of disease. Here, we use large clinical datasets to show the lack of correlation between BM blast burden and degree of cytopenias at the time of diagnosis. We develop a splenectomized xenograft model to demonstrate that transplantation of human primary AML into immunocompromised mice recapitulates the human disease course by induction of BM failure via depletion of mouse hematopoietic stem and progenitor populations. Using unbiased approaches, we show that AML-elaborated IL-6 acts to block erythroid differentiation at the proerythroblast stage and that blocking antibodies against human IL-6 can improve AML-induced anemia and prolong overall survival, suggesting a potential therapeutic approach.
View details for DOI 10.1126/scitranslmed.aax5104
View details for PubMedID 32269167
Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2.
The Journal of clinical investigation
Cancer-related anemia is present in over 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and red blood cell (RBC) transfusion-independence in AML patients treated with the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor, enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRIPSR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed CD71+ progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.
View details for DOI 10.1172/JCI133344
View details for PubMedID 31895700
Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience.
Leukemia & lymphoma
Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.
View details for DOI 10.1080/10428194.2020.1775214
View details for PubMedID 32543932
- Improved Outcomes of Octogenarians and Nonagenarians with Acute Myeloid Leukemia in the Era of Novel Therapies. American journal of hematology 2020
- Human Acute Myeloid Leukemia Inhibits Normal Erythroid Differentiation through the Paracrine Effects of IL-6 AMER SOC HEMATOLOGY. 2018
beta-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia
2015; 29 (12): 2328–37
Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples β-catenin expression from BCR-ABL1 kinase activity. In β-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of β-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic β-catenin levels, arguing against a role for β-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than β-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear β-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.
View details for DOI 10.1038/leu.2015.196
View details for Web of Science ID 000366393900007
View details for PubMedID 26202934
View details for PubMedCentralID PMC4675686
Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia
2015; 29 (3): 586–97
Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.
View details for DOI 10.1038/leu.2014.245
View details for Web of Science ID 000350734300008
View details for PubMedID 25134459
View details for PubMedCentralID PMC4334758
KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
2013; 73 (18): 5775–86
Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34(+)38(-) cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34(+)38(+) cells, SCF strongly induced pAKT(S473) in a phosphoinositide 3-kinase (PI3K)-dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKT(S473) levels remained low in CD34(+)38(-) cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34(+)38(-) compared with CD34(+)38(+) CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells.
View details for DOI 10.1158/0008-5472.CAN-13-1318
View details for Web of Science ID 000324806300017
View details for PubMedID 23887971
View details for PubMedCentralID PMC3894913
Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice
JOURNAL OF CLINICAL INVESTIGATION
2010; 120 (7): 2395–2405
Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-alpha transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.
View details for DOI 10.1172/JCI42011
View details for Web of Science ID 000279544000018
View details for PubMedID 20530874
View details for PubMedCentralID PMC2898601
Macrophages from 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-beta-Mediated up-regulation of SHIP1 expression
JOURNAL OF IMMUNOLOGY
2007; 179 (9): 6325–35
11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C(11)-keto-GCs to C(11)-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11betaHSD1(-/-) mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-alpha, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnMphi) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11betaHSD1(-/-) splnMphi results from an increased activation of NF-kappaB- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11betaHSD1(-/-) Mphi and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow Mphi (BMMphi) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11betaHSD1(+/+) and 11betaHSD1(-/-) BMMphi responded to LPS similarly. However, 11betaHSD1(-/-) BMMphi derived in the presence of elevated GC levels up-regulated SHIP1 expression and increased their capacity to produce inflammatory cytokines following their activation with LPS. These observations suggest the hyperresponsiveness of 11betaHSD1(-/-) splnMphi results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11betaHSD1(-/-) mice. GC-conditioning of BMMphi enhanced SHIP1 expression via up-regulation of bioactive TGF-beta. Consistently, TGF-beta protein expression was increased in unstimulated CD11b(-) cells residing in the BM and spleen of 11betaHSD1(-/-) mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of Mphi by augmenting SHIP1 expression through a TGF-beta-dependent mechanism.
View details for DOI 10.4049/jimmunol.179.9.6325
View details for Web of Science ID 000250388000081
View details for PubMedID 17947710
Glucocorticoid conditioning of myeloid progenitors enhances TLR4 signaling via negative regulation of the phosphatidylinositol 3-kinase-Akt pathway
JOURNAL OF IMMUNOLOGY
2007; 178 (4): 2517–26
The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Mphis) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-alpha, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-kappaB and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during Mphi differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Mphis purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.
View details for DOI 10.4049/jimmunol.178.4.2517
View details for Web of Science ID 000244026800062
View details for PubMedID 17277160
The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities
JOURNAL OF IMMUNOLOGY
2005; 174 (2): 879–89
The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes control the interconversion of active glucocorticoids (GCS) and their inactive 11-keto metabolites, a process commonly referred to as the cortisone/cortisol shuttle. Although the prereceptor metabolism of GCS by 11beta-HSD is well documented in a variety of cells and tissues, it has not yet been carefully investigated in the major cell types of the immune system. In this study, we demonstrate that 11beta-HSD1 transcripts, protein, and enzyme activities are actively expressed in murine CD4(+), CD8(+), and B220(+) lymphocytes, as well as CD11c(+) dendritic cells. Only reductase activity was observed in living cells, evidenced by the restricted conversion of cortisone to cortisol. Activation of CD4(+) T cells increased their 11beta-HSD1 activity, as did their polarization into Th1 or Th2 cells. CD4(+) T cells isolated from aged donors (>16 mo) had increased 11beta-HSD1 protein and an elevated capacity to convert cortisone to cortisol. The GCS generated in murine CD4(+) T cells from their inactive 11-keto metabolites could activate the GCS receptor, demonstrated by an up-regulation of IL-7Ralpha and GCS-induced leucine zipper gene expression. The presence of a functional 11beta-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis. Thus, the presence of 11beta-HSD1 provides an additional means to facilitate GCS influences over lymphocyte activities, uncoupled from the plasma concentration of GCS.
View details for DOI 10.4049/jimmunol.174.2.879
View details for Web of Science ID 000226360500038
View details for PubMedID 15634910
Peroxisome proliferator-activated receptor alpha negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation
JOURNAL OF IMMUNOLOGY
2003; 171 (1): 196–203
Expression of the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in resting lymphocytes was recently established, although the physiologic role(s) played by this nuclear hormone receptor in these cell types remains unresolved. In this study, we used CD4(+) T cells isolated from PPARalpha(-/-) and wild-type mice, as well as cell lines that constitutively express PPARalpha, in experiments designed to evaluate the role of this hormone receptor in the regulation of T cell function. We report that activated CD4(+) T cells lacking PPARalpha produce increased levels of IFN-gamma, but significantly lower levels of IL-2 when compared with activated wild-type CD4(+) T cells. Furthermore, we demonstrate that PPARalpha regulates the expression of these cytokines by CD4(+) T cells in part, through its ability to negatively regulate the transcription of T-bet. The induction of T-bet expression in CD4(+) T cells was determined to be positively influenced by p38 mitogen-activated protein (MAP) kinase activation, and the presence of unliganded PPARalpha effectively suppressed the phosphorylation of p38 MAP kinase. The activation of PPARalpha with highly specific ligands relaxed its capacity to suppress p38 MAP kinase phosphorylation and promoted T-bet expression. These results demonstrate a novel DNA-binding independent and agonist-controlled regulatory influence by the nuclear hormone receptor PPARalpha.
View details for DOI 10.4049/jimmunol.171.1.196
View details for Web of Science ID 000183674400025
View details for PubMedID 12816998