NIH Myeloid Malignancy Program

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Theme 1: Pre-clinical models to study MDS biology and therapy Investigators at the NCI CCR have developed an in vivo model for MDS, which has been used by numerous investigators to study MDS biology, including the role of the immune system and an inflammatory microenvironment in the development and progression of MDS. Moreover, this model was used to provide proof of concept for the development of luspatercept, the only new drug to receive FDA approval for the treatment of MDS in the past decade. An NCI inter-divisional agreement has been formed between the DCTD and CCR to study the in vivo efficacy of novel DNA hypomethylating agents (HMA) using this model, and a CRADA with Tolero Pharmaceuticals to use this model to study the CDK9 kinase inhibitor alvocidib has been signed recently (PI Peter Aplan). Additional ongoing or planned studies are focused on the MDS/AML microenvironment, and determining how AML cells can influence or "shape" the microenvironment, which in turn influences the number and function of co-existing normal hematopoietic stem and progenitor cells (HSPC). Furthermore, there is a growing understanding of the importance of myeloid and stromal cells in the regulation of the bone marrow niche environment during normal development/aging and pathology. Approaches that rebalance this dysregulated microenvironment may, in combination with other therapies, prevent disease progression or limit relapse. For example, a recent clinical trial of pexidartinib, a CSF1R inhibitor in recurrent, refractory leukemias and solid tumors suggests that approaches that target the immune suppressive microenvironment may be effective in the setting of MDS/AML and other dysregulated bone marrow microenvironments (PI Rosandra Kaplan). Theme 2: Post-transcriptional regulation in MDS/AML Changes in post-transcriptional regulation are a hallmark of myeloid diseases. For example, 60% of MDS patients have somatic mutations in the core spliceosomal machinery, and spliceosome mutations are enriched in relapsed-refractory AML. Similarly, germline mutations in the translation and ribosome biogenesis machinery selectively result in anemia and other defects in myelopoiesis. We hypothesize that characterization of post-transcriptional regulation (splicing, translation) in immunological sub-populations, correlated with underlying DNA mutations, will reveal new pathways of disease progression and treatment. For example, we will identify how splicing factor mutations modify the immune microenvironment and how spurious translation might generate neo-antigens, both of which contribute to success/failure of immunotherapy (PI Dan Larson). Theme 3: Germline predispositions to myeloid malignancy RUNX1 Familial Platelet Disorder: Autosomal dominant germline RUNX1 mutations are associated with qualitative and quantitative platelet disorders and a 20-50% lifetime risk of hematologic malignancy. Currently, there is a poor understanding of the variability in penetrance of cancer development across different families and even among individuals within the same family. In addition, the disease manifestations outside of the hematopoietic tissues have not been studied systematically. We started a comprehensive natural history study on patients with germline RUNX1 mutations last year, which has quickly become the largest such study in the world with enrollment of 50 patients and 48 family controls from 25 families. We perform comprehensive genomic studies and extensive phenotyping. We have identified previously unrecognized allergic, immunologic, gastrointestinal, and pulmonary symptoms in many of our patients, with consultation of clinical and research faculty from 6 ICs. The RUNX1 natural history study is shaping up to be an international hub for patient referrals, a central collection of data and patient samples, and a focal point for collaborative clinical and translational studies to understand the disease mechanism, to identify biomarkers for disease progression, and to improve patient monitoring, management, and treatment (PIs Lea Cunningham, Paul Liu). Theme 4: Role of the immune system in control of MDS/AML CD123: Treating relapsed/refractory AML/MDS is a challenge and there is a major unmet need for new therapies to target the chemo-resistant cells responsible for relapse. CD123 (IL3R) is expressed on most AML/MDS cells and is enriched within the leukemic stem cell (LSC) compartment. We have engineered T cells (CD123-ENG) to constitutively secrete a bispecific small molecule (CD123xCD3) which directs T cell cytotoxicity to cells with surface expression of CD123.26 Unlike trials of CD123-BiTEs requiring several weeks of continuous infusion due to their short half-life,27 CD123-ENG T cells are given as a single dose, long-lived therapy which enables continuous in vivo secretion of the CD123xCD3 bispecific engager molecule. We propose a first-in-class phase I clinical trial of CD123-ENG for patients with AML/high-risk MDS with correlative studies including next generation sequencing to track the ability of ENG-T cells to eradicate very low levels of measurable residual disease, a key factor predicting outcome in these patients28 (PI Noa Holtzman). Interleukin-8 (IL-8): Cytokine profile analysis in the peripheral blood and bone marrow of MDS patients identified a strong correlation between upregulated IL-8 levels and the MDS phenotype,33 even after treatment with hypomethylating agents (HMA).34 Further, both IL-8 and CXCR2 are overexpressed in purified MDS/AML stem cells and granulocyte-macrophage progenitor cells.35 A comprehensive proteomics profiling study identified IL-8 as the central molecule in the network of more than 150 dysregulated proteins in the bone marrow of patients with AML, suggesting that IL-8 is a promising therapeutic target. Recently, CCR intramural investigators identified a direct link between a mutation in the splicing factor U2AF1 and post-transcriptional regulation of IL-8.9 We propose a phase 1/2 clinical trial of sequential treatment with HMA and humanized anti-IL-8 antibody in patients with MDS (PIs Pavletic, Larson). The anti-IL8 treatment study and the MDS natural history clinical study have both been opened in 2023.