Siddhartha Jaiswal is a recent faculty recruit to Stanford in the Department of Pathology. He is no stranger to the Farm, having also obtained undergraduate, medical, and doctorate degrees at Stanford. His thesis work in Irv Weissman's lab focused on understanding the role of the innate immune signaling ligand, CD47, in macrophage tumor immunosurveillance. This work formed the rationale for the therapeutic targeting of CD47 in human cancer, which is currently in clinical trials at Stanford and elsewhere.

Dr. Jaiswal subsequently completed residency and fellowship training in pathology at the Massachusetts General Hospital and Harvard Medical School. As a post-doctoral fellow at the Broad Institute, he identified a common, pre-malignant state for blood cancers by reanalysis of large sequencing datasets. This condition, termed "clonal hematopoiesis", is characterized by the presence of stem cell clones harboring certain somatic mutations, primarily in genes involved in epigenetic regulation of hematopoiesis. Clonal hematopoiesis is prevalent in the aging population and increases the risk of not only blood cancer, but also cardiovascular disease and overall mortality. Understanding the biology of these mutations and how they contribute to the development of cancer and other age-related diseases is the current focus of work in his lab.

Clinical Focus

  • Pathology
  • Transfusion Medicine
  • Genomics and Molecular Pathology

Academic Appointments

Honors & Awards

  • Career Award for Medical Scientists, Burroughs Wellcome Fund (2016)
  • BroadIgnite Scholar, Broad Institute of MIT and Harvard (2016)
  • Paul E. Strandjord Young Investigator Award, ACLPS (2014)
  • Firestone Medal for Excellence in Research, Stanford University (2000)
  • Phi Beta Kappa, Stanford University (2000)

Professional Education

  • Fellowship, Harvard Medical School, Transfusion Medicine (2013)
  • Residency, Massachusetts General Hospital, Clinical Pathology (2014)
  • PhD, Stanford University School of Medicine, Immunology (2010)
  • MD, Stanford University School of Medicine (2010)
  • BS, Stanford University, Biological Sciences (2000)


  • Siddhartha Jaiswal, Irving L. Weissman, Ravindra Majeti, Mark P. Chao. "United States Patent 8562997 B2 Methods of treating acute myeloid leukemia by blocking CD47", The Board Of Trustees Of The Leland Stanford Junior University, Oct 22, 2013

Research & Scholarship

Current Research and Scholarly Interests

Somatic Mutations in Aging

Aging is associated with an increased incidence of cancer and several other diseases. As a post-doctoral fellow, Dr. Jaiswal identified a common age-related disorder of the blood characterized by the acquisition of certain somatic mutations in hematopoietic stem cells (Jaiswal et al., NEJM 2014). These mutations allow stem cell clones to expand relative to normal stem cells; this clonal expansion is termed "clonal hematopoiesis of indeterminate potential", or CHIP (Steensma et al., Blood 2015).

The most commonly found mutations in CHIP are in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1). CHIP is very rare in the young, but becomes common with aging. Between 10-30% of the elderly have a clonal mutation meeting the definition of CHIP. Those with CHIP are at markedly increased risk of developing hematological malignancies such as myelodysplastic syndrome, acute myeloid leukemia, and lymphoma.

Surprisingly, CHIP is also associated with increased risk of atherosclerotic cardiovascular disease, and this relationship is thought to be causal based on mouse models (Jaiswal et al., NEJM 2017). Mechanistically, the mutations in CHIP lead to increased expression of inflammatory gene modules in mature immune cells such as macrophages. These immune effector cells are derived from the mutated hematopoietic stem cells in the marrow, hence they also harbor the CHIP-related mutations.

These observations suggest that somatic mutations in hematopoietic stem cells that arise during aging may have a variety of effects on health. The lab seeks to understand the biology and clinical impact of these mutations, as described in the projects below.


  • Using human population genetics to learn the health associations of clonal hematopoiesis.

    Chronic inflammation seems to be a common feature of human aging, but the reasons for this are unclear. We hypothesize that CHIP might actually underlie much of the age-associated inflammation seen in humans. Consequently, CHIP might modulate the risk of several diseases of aging.


    Stanford University

  • Mechanistic studies on the role of DNA methylation in clonal expansion of stem cells and dysregulated inflammation.

    It is striking that the two most frequently mutated genes in CHIP, DNMT3A and TET2, are involved in DNA methylation dynamics. We hypothesize that these mutations lead to alterations in DNA methylation that promote self-renewal and inflammatory transcriptional programs. Using model systems, we will uncover the role of methylation in these programs.


    Stanford University

  • Characterization of hematopoietic and immune cell subsets from humans with CHIP.

    Much of our knowledge of the effects of mutations found in CHIP comes from mouse models because individuals with CHIP do not have overt disease, hence they do not enroll in clinical studies. We seek to prospectively identify individuals with CHIP to learn more about how these mutations affect stem cell and immune cell function in a native human context.


    Stanford University

  • Identification of novel therapeutics to treat CHIP and/or its associated diseases.

    If CHIP mutations lead to aberrant stem cell and immune cell function by altering gene expression, it should be possible to reverse these effects therapeutically. We aim to identify suitable targets for intervention to prevent stem cell expansion and inflammation associated with CHIP.


    Stanford University


2017-18 Courses

Graduate and Fellowship Programs


All Publications

  • Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. The New England journal of medicine Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., McConkey, M., Gupta, N., Gabriel, S., Ardissino, D., Baber, U., Mehran, R., Fuster, V., Danesh, J., Frossard, P., Saleheen, D., Melander, O., Sukhova, G. K., Neuberg, D., Libby, P., Kathiresan, S., Ebert, B. L. 2017; 377 (2): 111–21


    Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

    View details for DOI 10.1056/NEJMoa1701719

    View details for PubMedID 28636844

  • Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes BLOOD Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., Ebert, B. L. 2015; 126 (1): 9-16


    Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

    View details for DOI 10.1182/blood-2015-03-631747

    View details for Web of Science ID 000357696200006

    View details for PubMedID 25931582

    View details for PubMedCentralID PMC4624443

  • Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes NEW ENGLAND JOURNAL OF MEDICINE Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., Higgins, J. M., Moltchanov, V., Kuo, F. C., Kluk, M. J., Henderson, B., Kinnunen, L., Koistinen, H. A., Ladenvall, C., Getz, G., Correa, A., Banahan, B. F., Gabriel, S., Kathiresan, S., Stringham, H. M., McCarthy, M. I., Boehnke, M., Tuomilehto, J., Haiman, C., Groop, L., Atzmon, G., Wilson, J. G., Neuberg, D., Altshuler, D., Ebert, B. L. 2014; 371 (26): 2488-2498


    The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events.Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8).Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

    View details for DOI 10.1056/NEJMoa1408617

    View details for Web of Science ID 000346920300008

    View details for PubMedID 25426837

    View details for PubMedCentralID PMC4306669

  • CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis CELL Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., Traver, D., van Rooijen, N., Weissman, I. L. 2009; 138 (2): 271-285


    Macrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPalpha, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently upregulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively upregulated on mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 upregulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.

    View details for DOI 10.1016/j.cell.2009.05.046

    View details for Web of Science ID 000268277000010

    View details for PubMedID 19632178

    View details for PubMedCentralID PMC2775564

  • Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma JOURNAL OF CLINICAL ONCOLOGY Gibson, C. J., Lindsley, R. C., Tchekmedyian, V., Mar, B. G., Shi, J., Jaiswal, S., Bosworth, A., Francisco, L., He, J., Bansal, A., Morgan, E. A., LaCasce, A. S., Freedman, A. S., Fisher, D. C., Jacobsen, E., Armand, P., Alyea, E. P., Koreth, J., Ho, V., Soiffer, R. J., Antin, J. H., Ritz, J., Nikiforow, S., Forman, S. J., Michor, F., Neuberg, D., Bhatia, R., Bhatia, S., Ebert, B. L. 2017; 35 (14): 1598-?


    Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

    View details for DOI 10.1200/JCO.2016.71.6712

    View details for Web of Science ID 000400811200016

    View details for PubMedID 28068180

    View details for PubMedCentralID PMC5455707

  • Clonal hematopoiesis SEMINARS IN HEMATOLOGY Jan, M., Ebert, B. L., Jaiswal, S. 2017; 54 (1): 43-50


    Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease.

    View details for DOI 10.1053/j.seminhematol.2016.10.002

    View details for Web of Science ID 000393445800008

    View details for PubMedID 28088988

  • Clonal Hematopoiesis and Atherosclerosis. The New England journal of medicine Jaiswal, S., Natarajan, P., Ebert, B. L. 2017; 377 (14): 1401–2

    View details for DOI 10.1056/NEJMc1710381

    View details for PubMedID 28976867

  • Clonal Hematopoiesis and Blood-Cancer Risk NEW ENGLAND JOURNAL OF MEDICINE Yan, B., Ban, K., Chng, W. 2015; 372 (11): 1071-1071

    View details for DOI 10.1056/NEJMc1500684

    View details for Web of Science ID 000350797300014

    View details for PubMedID 25760362

  • Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance NATURE MEDICINE Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S. J., Javidi-Sharifi, N., Maciejewski, J. P., Jaiswal, S., Ebert, B. L., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. 2015; 21 (1): 71-75


    Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

    View details for DOI 10.1038/nm.3751

    View details for Web of Science ID 000348408000015

    View details for PubMedID 25485910

    View details for PubMedCentralID PMC4289115

  • MDS Is a Stem Cell Disorder After All CANCER CELL Jaiswal, S., Ebert, B. L. 2014; 25 (6): 713-714


    Myelodysplastic syndrome (MDS) has long been presumed to be a stem cell disorder, but rigorous formal proof has been lacking. In this issue of Cancer Cell, Woll and colleagues demonstrate that driver mutations occurring in MDS definitively occur in cells with a stem cell phenotype.

    View details for DOI 10.1016/j.ccr.2014.06.001

    View details for Web of Science ID 000337709600002

    View details for PubMedID 24937455

  • Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice JOURNAL OF EXPERIMENTAL MEDICINE Han, M. H., Lundgren, D. H., Jaiswal, S., Chao, M., Graham, K. L., Garris, C. S., Axtell, R. C., Ho, P. P., Lock, C. B., Woodard, J. I., Brownell, S. E., Zoudilova, M., Hunt, J. F., Baranzini, S. E., Butcher, E. C., Raine, C. S., Sobel, R. A., Han, D. K., Weissman, I., Steinman, L. 2012; 209 (7): 1325-1334


    Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.

    View details for DOI 10.1084/jem.20101974

    View details for Web of Science ID 000306174300008

    View details for PubMedID 22734047

    View details for PubMedCentralID PMC3405500

  • The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. B., Alizadeh, A. A., Clarke, M. F., Weissman, I. L. 2012; 109 (17): 6662-6667


    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

    View details for DOI 10.1073/pnas.1121623109

    View details for Web of Science ID 000303249100065

    View details for PubMedID 22451913

    View details for PubMedCentralID PMC3340046

  • Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47 SCIENCE TRANSLATIONAL MEDICINE Chao, M. P., Jaiswal, S., Weissman-Tsukamoto, R., Alizadeh, A. A., Gentles, A. J., Volkmer, J., Weiskopf, K., Willingham, S. B., Raveh, T., Park, C. Y., Majeti, R., Weissman, I. L. 2010; 2 (63)


    Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro- and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin's lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor-related protein, on phagocytic cells prevented anti-CD47 antibody-mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin's lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro- and anti-phagocytic signals in the immune evasion of cancer.

    View details for DOI 10.1126/scitranslmed.3001375

    View details for Web of Science ID 000288444900003

    View details for PubMedID 21178137

  • Macrophages as mediators of tumor immunosurveillance TRENDS IN IMMUNOLOGY Jaiswal, S., Chao, M. P., Majeti, R., Weissman, I. L. 2010; 31 (6): 212-219


    Tumor immunosurveillance is a well-established mechanism for regulation of tumor growth. In this regard, most studies have focused on the role of T- and NK-cells as the critical immune effector cells. However, macrophages play a major role in the recognition and clearance of foreign, aged, and damaged cells. Macrophage phagocytosis is negatively regulated via the receptor SIRPalpha upon binding to CD47, a ubiquitously expressed protein. We recently showed that CD47 is up-regulated in myeloid leukemia and migrating hematopoietic progenitors, and that the level of protein expression correlates with the ability to evade phagocytosis. These results implicate macrophages in the immunosurveillance of hematopoietic cells and leukemias. The ability of macrophages to phagocytose tumor cells might be exploited therapeutically by blocking the CD47-SIRPalpha interaction.

    View details for DOI 10.1016/

    View details for Web of Science ID 000279427000002

    View details for PubMedID 20452821

    View details for PubMedCentralID PMC3646798

  • CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells CELL Majeti, R., Chao, M. P., Alizadeh, A. A., Pang, W. W., Jaiswal, S., Gibbs, K. D., van Rooijen, N., Weissman, I. L. 2009; 138 (2): 286-299


    Acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells (LSC). We hypothesized that increased CD47 expression on human AML LSC contributes to pathogenesis by inhibiting their phagocytosis through the interaction of CD47 with an inhibitory receptor on phagocytes. We found that CD47 was more highly expressed on AML LSC than their normal counterparts, and that increased CD47 expression predicted worse overall survival in three independent cohorts of adult AML patients. Furthermore, blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Finally, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted AML LSC. In summary, increased CD47 expression is an independent, poor prognostic factor that can be targeted on human AML stem cells with blocking monoclonal antibodies capable of enabling phagocytosis of LSC.

    View details for DOI 10.1016/j.cell.2009.05.045

    View details for Web of Science ID 000268277000011

    View details for PubMedID 19632179

    View details for PubMedCentralID PMC2726837

  • Hematopoietic Stem and Progenitor Cells and the Inflammatory Response 6th International Cancer Vaccine Symposium Jaiswal, S., Weissman, I. L. BLACKWELL PUBLISHING. 2009: 118–121


    Cells of the vertebrate immune system are continuously regenerated by division of hematopoietic stem cells (HSCs) into differentiated effector cells. Classically, HSCs were thought to reside primarily in the bone marrow niche where they produced mature progeny that migrated from the marrow to repopulate the peripheral immune system. However, emerging evidence has established that hematopoietic stem and progenitor cells (HSPCs) are themselves mobile and able to repopulate ectopic niches and contribute more directly to inflammatory responses in the periphery. How the HSPCs remain immune to destruction in a toxic inflammatory milieu is unknown.

    View details for DOI 10.1111/j.1749-6632.2009.04930.x

    View details for Web of Science ID 000271828500015

    View details for PubMedID 19769744

  • Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jaiswal, S., Traver, D., Miyamoto, T., Akashi, K., Lagasse, E., Weissman, I. L. 2003; 100 (17): 10002-10007


    Chronic myelogenous leukemia is a myeloproliferative disorder (MPD) that, over time, progresses to acute leukemia. Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny. Chronic myelogenous leukemia is therefore classified as an HSC disorder in which a clone of multipotent HSCs is likely to be malignantly transformed, although direct evidence for malignant t(9;22)+ HSCs is lacking. To test whether HSC malignancy is required, we generated hMRP8p210BCR/ABL transgenic mice in which expression of BCR/ABL is absent in HSCs and targeted exclusively to myeloid progenitors and their myelomonocytic progeny. Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis. To address whether additional oncogenic events are required for progression to acute disease, we crossed hMRP8p210BCR/ABL mice to apoptosis-resistant hMRP8BCL-2 mice. Of 18 double-transgenic animals, 9 developed acute myeloid leukemias that were transplantable to wild-type recipients. Taken together, these data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.

    View details for DOI 10.1073/pnas.1633833100

    View details for Web of Science ID 000184926000069

    View details for PubMedID 12890867

    View details for PubMedCentralID PMC187741