About

Erik Ranheim is a Professor and Department Chair in the Department of Pathology and Laboratory Medicine at the University of Wisconsin School of Medicine and Public Health. His research focuses on two broad areas: the interaction of the immune system with tumor cells and the role of the frizzled/wnt/beta-catenin pathway in normal and neoplastic lymphoid development and function. Dr. Ranheim's laboratory investigates the mechanisms of immune system and tumor interactions, particularly why tumors often prevail despite the presence of anti-tumor lymphocytes, through studies in mouse models and human patients with B cell leukemia/lymphoma and melanoma, in collaboration with the UW Carbone Cancer Center. Additionally, his work on the frizzled/wnt pathway explores its role in regulating beta-catenin levels within cells, which has implications in human tumors such as colon cancer and familial polyposis syndrome. His research has demonstrated that this pathway is critical for the development of lymphoma and leukemia in mouse models and may influence the survival and growth of malignant B cells.

Research topics

• Biology
• Immunology
• Genetics
• Cancer research
• Pathology
• Medicine
• Molecular biology
• Oncology
• Virology
• Cell biology
• Medical emergency

Selected publications

• Boosting anti-tumor immunity in NRAS;ASXL1-driven Acute Myeloid Leukemia through combined inhibition of MEK and HDACs.

  Blood · 2025-11-03

  articleOpen access

  Abstract Acute myeloid leukemia (AML) is a highly aggressive blood cancer with 5-year overall survival rates of ~30%. Its treatment outcome is greatly influenced by leukemia driver mutations and T cell phenotypes at the time of diagnosis. Oncogenic NRAS mutations are associated with AML progression, resistance to multiple targeted therapies, and treatment failure in AML. ASXL1 mutations are significantly associated with NRAS mutations in chronic myelomonocytic leukemia (CMML) and correlate with poor prognosis in myeloid malignancies, including AML. We have previously developed an NRAS; ASXL1 mouse model in which loss of ASXL1 co-operates with oncogenic NRAS to promote CMML transformation to secondary AML (NA-AML). NA-AML mice were characterized by an immune-suppressive microenvironment resulting in exhaustion of dysfunctional CD4 and CD8 T cells. Targeting hyperactive RAS/MEK signaling via trametinib (Tra, a MEK inhibitor) attenuated T cell exhaustion and prolonged the survival of NA-AML mice, cementing the role of T cells in modulating AML treatment outcomes. To further improve the efficacy of Tra, we carried out a re-purpose screen of ~2,500 drugs, either approved by FDA or currently under clinical development. We identified and validated inhibition of MEK/ERK signaling via Tra and histone deacetylases (HDACs) via quisinostat (Qui, a 2nd generation of HDAC inhibitor) as an effective combo therapy against mouse and human primary NA-AML cells and non-NA human AML cell lines in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged survival. Surprisingly, TQ only provided moderate survival benefits in immunodeficient NSG mice and in immunocompetent mice with T-cell depletion, suggesting T cells as the primary target of TQ. Further analyses revealed that TQ played a dual role in modulating the epigenomes of both NA-AML and T cells. In NA-AML cells, TQ led to global increase of H3K27Ac level and concomitant decrease of H3K27me3 level. Moreover, TQ upregulated MHC-I and MHC-II expression. Hyperactivation of the JAK/STAT1 pathway, partially through Tra, promoted MHC-I expression, while Qui-mediated HDAC inhibition resulted in upregulation of CIITA, a master transcription co-activator driving MHC-II expression. In CD4 and CD8 T cells, scRNA-Seq and spectral flow cytometry analyses revealed upregulation of H3K27Ac and H3K4me1, elevated JAK/STAT1 signaling, enhanced differentiation of IL2-secreting anti-leukemia Th1 cells, decreased T cell exhaustion, upregulation of genes promoting T cell survival, as well as increased activation and expansion of cytotoxic cluster in T central memory (Tcm) and effector memory (Tem) cells. Furthermore, leukemia:T cell co-cultures showed significantly enhanced cytotoxicity of TQ-treated CD4 and CD8 T cells, which was MHC-dependent and enriched in both Tcm and Tem cells. More importantly, TQ supported expansion and improvement of anti-leukemia killing in AML-associated T cells in vitro, suggesting that autologous T cell transfer may be a useful approach to explore in the future. Not surprisingly, the remaining leukemia cells in the co-cultures and in the moribund TQ-treated NA-AML mice were predominantly MHC-I- MHC-II-. Our results suggest that we must seek additional MHC-independent anti-cancer mechanisms to further improve the therapeutic effects of TQ. We are currently evaluating the effects of combining TQ with anti-TIGIT immune checkpoint blockade to activate endogenous non-MHC restricted natural killer cells in NA-AML mice.

  PublisherOA PDFDOI

• Abstract 2226: Combined inhibition of MEK and HDACs improves the cytotoxicity of CD4 and CD8 T cells in NRAS;ASXL1-driven acute myeloid leukemia mice

  Cancer Research · 2025-04-21

  article

  Abstract Acute myeloid leukemia (AML) is a heterogeneous malignant blood cancer that occurs mainly in the elderly. Its treatment outcome is greatly influenced by leukemia-driving mutations. Oncogenic NRAS mutations are associated with both AML progression and multi-drug resistance and treatment failure in AML. We have previously developed a NRAS; ASXL1-driven secondary AML (NA-AML) mouse model, which is characterized by a suppressive immune microenvironment resulting in reduced leukemia killing activities of T cells. Targeting hyperactive RAS/MEK signaling via trametinib (T, a MEK inhibitor) attenuates the exhaustion of CD8 T cells and prolongs the survival of NA-AML mice. To further boost the efficacy of T, we performed a re-purpose screen of ∼2, 500 drugs, either approved by FDA for treating various human diseases or currently under clinical evaluation, in the absence or presence of T. We identified that quisinostat (Q), a 2nd generation of HDAC inhibitor, potently inhibited the growth of both mouse and human NA leukemia cells and significantly synergized with T in vitro. In addition, combined T and Q (TQ) downregulated AP-1 transcription factors and expression of immune checkpoint ligands (PD-L1/L2, CD80, and CD86) while upregulated expression of MHC I/II in mouse NA-AML cells. We further validated our results in NA-AML mice. Vehicle (Veh) -treated mice rapidly succumbed to AML and died within 4-5 weeks post-treatment. T alone and Q alone slowed down AML progression and prolonged the survival of leukemia mice, while all TQ-treated mice remained alive ∼22 weeks post-treatment. Surprisingly, TQ only provided moderate survival benefits in immunodeficient NSG mice engrafted with NA-AML cells, suggesting an important role of cytotoxic T cells in TQ-mediated AML alleviation. We then analyzed CD4 and CD8 T cells from moribund vehicle-treated mice and age-matched drug-treated mice. TQ decreased the exhaustion of CD4 and CD8 T cells and expanded the activated effector/memory T (Tem) cells. Single-cell RNA-Seq analysis showed increased expression of gene signatures associated with cytotoxicity of Tem cells, including CXCR3 and CXCR5. Consistent with these findings, leukemia: T cell co-culture experiments demonstrated significantly enhanced cytotoxicity of TQ-treated CD4 and CD8 T cells, which appeared to be mediated by increased expression of MHC I and II in AML cells. We are currently pursuing the underlying molecular mechanisms. Our data provide a strong rationale to develop immunotherapies via epigenetic modulation of both leukemia and leukemia-associated T cells. Citation Format: Meher Gayatri Bolisetti, Jing Li, Bei Jia, Esra’a Keewan, Erik A. Ranheim, Kalyan V.G Nadiminti, Hong Zheng, Xiaona You, Jing Zhang. Combined inhibition of MEK and HDACs improves the cytotoxicity of CD4 and CD8 T cells in NRAS;ASXL1-driven acute myeloid leukemia mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2226.

  PublisherDOI

• To Grade or Not to Grade (the Quiz): The Impact of Two Formative Assessment Grading Approaches on Summative Assessment Outcomes in an Integrated Pre-clinical Curriculum

  Medical Science Educator · 2024-05-07 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Subperiosteal delivery of transforming growth factor beta 1 and human growth hormone from mineralized <scp>PCL</scp> films

  Journal of Biomedical Materials Research Part A · 2024-03-26

  article

  The ability to locally deliver bioactive molecules to distinct regions of the skeleton may provide a novel means by which to improve fracture healing, treat neoplasms or infections, or modulate growth. In this study, we constructed single-sided mineral-coated poly-ε-caprolactone membranes capable of binding and releasing transforming growth factor beta 1 (TGF-β1) and human growth hormone (hGH). After demonstrating biological activity in vitro and characterization of their release, these thin bioabsorbable membranes were surgically implanted using an immature rabbit model. Membranes were circumferentially wrapped under the periosteum, thus placed in direct contact with the proximal metaphysis to assess its bioactivity in vivo. The direct effects on the metaphyseal bone, bone marrow, and overlying periosteum were assessed using radiography and histology. Effects of membrane placement at the tibial growth plate were assessed via physeal heights, tibial growth rates (pulsed fluorochrome labeling), and tibial lengths. Subperiosteal placement of the mineralized membranes induced greater local chondrogenesis in the plain mineral and TGF-β1 samples than the hGH. More exuberant and circumferential ossification was seen in the TGF-β1 treated tibiae. The TGF-β1 membranes also induced hypocellularity of the bone marrow with characteristics of gelatinous degeneration not seen in the other groups. While the proximal tibial growth plates were taller in the hGH treated than TGF-β1, no differences in growth rates or overall tibial lengths were found. In conclusion, these data demonstrate the feasibility of using bioabsorbable mineral coated membranes to deliver biologically active compounds subperiosteally in a sustained fashion to affect cells at the insertion site, bone marrow, and even growth plate.

  PublisherDOI

• Beyond the Screen: Navigating Remote Work within Medicine

  Clinical Chemistry · 2024-06-14 · 1 citations

  articleSenior author

  The onset of the COVID-19 global pandemic in 2020 brought abrupt changes to how people lived their lives and interacted with society. Many activities and jobs that did not require face-to-face interactions were shifted to remote or distanced formats. While certain aspects of healthcare require in-person interactions, the pandemic triggered a rapid expansion of telemedicine for areas where it was feasible to do so. Additionally, many non-patient facing roles that did not necessitate an onsite presence were converted to remote work. [...]

  PublisherDOI

• Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice

  PLoS Pathogens · 2024-04-15 · 8 citations

  articleOpen accessCorresponding

  Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.

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• Administration of intratumoral GD2-directed interleukin-2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma

  Melanoma Research · 2024-05-20 · 6 citations

  articleOpen access

  Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8 Gy fraction (arm A) or three 8 Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral-immunocytokine at 12 mg/m 2 on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral-immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.

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• Data from A Three-Arm Randomized Phase II Study of Bendamustine/Rituximab with Bortezomib Induction or Lenalidomide Continuation in Untreated Follicular Lymphoma: ECOG-ACRIN E2408

  2023-03-31

  preprintOpen access

  &lt;div&gt;AbstractPurpose:&lt;p&gt;We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL).&lt;/p&gt;Patients and Methods:&lt;p&gt;Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683).&lt;/p&gt;Results:&lt;p&gt;For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (&lt;i&gt;P&lt;/i&gt; = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (&lt;i&gt;P&lt;/i&gt; = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs &lt;1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001), and febrile neutropenia 10% versus 2%, respectively (&lt;i&gt;P&lt;/i&gt; = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (&lt;i&gt;P&lt;/i&gt; = 0.36) with OS rates of 87%, 90%, and 84%, respectively (&lt;i&gt;P&lt;/i&gt; = 0.79). For prognostication, CR rate and POD-24 were associated with survival.&lt;/p&gt;Conclusions:&lt;p&gt;Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.&lt;/p&gt;&lt;/div&gt;

  PublisherDOI

• Supplemental Figure SF-03 from Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2

  2023-03-31

  preprintOpen access

  &lt;p&gt;Hu14.18-IL2 Treatment Improves Direct Positive Correlations between Myeloid and Lymphoid Cells as indicated by ssGSEA Signatures&lt;/p&gt;

  PublisherDOI

• Supplemental Figure SF-13 from Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2

  2023-03-31

  preprintOpen access

  &lt;p&gt;Expression of Melanoma Marker Genes Portends Unfavorable RFS and OS in Group A but not Group B. Expression of Apoptotic Marker Genes Portends Favorable RFS and OS in Group A but not Group B.&lt;/p&gt;

  PublisherDOI

Recent grants

• NIH Grant K08CA090450

  NIH · $664k · 2008

Frequent coauthors

• Paul M. Sondel

  University of Wisconsin–Madison

  73 shared

• Mark R. Albertini

  University of Wisconsin Carbone Cancer Center

  62 shared

• Jacquelyn A. Hank

  University of Wisconsin–Madison

  56 shared

• Cindy Zuleger

  University of Wisconsin Carbone Cancer Center

  55 shared

• Richard K. Yang

  47 shared

• KyungMann Kim

  University of Wisconsin–Madison

  46 shared

• Zachary S. Morris

  University of Wisconsin–Madison

  45 shared

• Amy K. Erbe

  University of Wisconsin–Madison

  42 shared