Two Fred Hutch students receive American Society for Hematology graduate awards

Elana Thieme and Mark Mendoza, fourth-year graduate students in the Molecular and Cell Biology (MCB) PhD Program jointly administered by Fred Hutch Cancer Center and the University of Washington, have received graduate awards from the American Society for Hematology (ASH). Their research projects examine different aspects of gene expression in immune system cells that can lead to bone marrow disorders, including myelodysplastic syndromes and pediatric leukemia.

Thieme received the ASH Graduate Hematology Award and Mendoza received the ASH Hematology Inclusion Pathway (HIP) Graduate Student Award. Each award provides an annual stipend of $40,000 for two years to be used for tuition, research, training-related expenses and travel to the ASH Annual Meeting and Exposition. Thieme and Mendoza will receive their awards at this year’s ASH meeting, to be held in Orlando, Florida from December 6-9, 2025.

“The ASH Graduate Hematology Award started in 2022 on the recommendation of a task force advocating for more basic [science] PhD trainees within the ASH community,” said Stanley C. Lee, PhD, associate professor in the Translational Science and Therapeutics Division, and one of Thieme’s PhD mentors. Lee’s student Rasika Venkataraman also received this award last year. 

Traditionally, few PhD awards are available to hematology trainees, apart from government funding sources such as the National Institutes for Health (NIH) and the National Science Foundation (NSF). The ASH awards provide support for students who have progressed far enough in their dissertation projects to have generated promising preliminary data to fund their doctoral research project.

“Having an award like this, especially in hematology, will really benefit students at all levels [of their training],” Lee said. 

Unraveling the mystery of alternative gene splicing in myelodysplastic syndromes

Thieme’s ASH project looks at new ways to understand how RNA, which carries genetic instructions for making cellular proteins from a cell’s nucleus into the cytoplasm, is “spliced” in alternative ways that can sometimes cause disease. 

Alternative splicing is a normal occurrence in healthy cells that allows a single gene to drive the manufacture of multiple cellular proteins. However, alternative splicing events can also be driven by gene mutations.

One potential outcome of mutation-driven alternative splicing is a collection of disorders known as myelodysplastic syndromes, or MDS, in which bone marrow cells that do not act normally (such as improperly dividing, or not differentiating fully into mature immune system cells) are found alongside healthy cells. (The term “dysplasia” is used to denote a tissue or organ with some number of abnormal cells.)

Thieme will examine MDS cells with a mutation in the SRSF2 (serine- and arginine-rich splicing factor 2) gene. 

While dysplasias themselves are not cancerous, and some are considered mild, MDS is a difficult syndrome to treat, with a 5-year survival rate of only 37%. It often appears in older patients who are not good candidates for bone marrow transplantation due to their age and infirmities. The need for new treatments is therefore critical.

Thieme will work with Lee and co-mentor Manu Setty, PhD, assistant professor in both the Basic Sciences Division and in the Herbold Computational Biology Program of the Public Health Sciences Division.

She will devise a computational method to examine how alternative splicing in MDS cells with the SRSF2 mutation can change, depending on whether the splicing event occurs in a stem cell (a type of blood cell that gives rise to all other types of blood cells) or further down a cell’s developmental pathway when it differentiates into a “progenitor” cell that has developed far enough to be committed to a particular cell lineage.

Thieme will use a technology known as long-read single-cell RNA sequencing, or long-read scRNA-seq, to examine the entire set of RNA transcripts that enter an MDS cell’s cytoplasm, where protein assembly occurs. From there she will map the alternatively-spliced transcripts back to the original genome found in the cell’s DNA to determine how alternative splicing events in MDS cells affect the fate of the cell and the progression of MDS.

“The tricky part in these patients is that, unlike one mutation in one cell type, in MDS patients the mutation starts in the stem cell and goes all the way down to the mature blood cell lineages,” Thieme explained. “That’s really complicated to study, because each cell type has its own splicing pattern. The SRSF2 mutation is going to affect every cell type [in MDS] differently, and so far, nobody has been able to study all of these different cells at the same time.” 

Thieme aims to solve that problem by using computational tools to analyze long-read RNA sequences from multiple lineages of MDS cells. Instead of focusing on one specific lineage or cell type, such as mature myeloid cells or mature erythroid cells, Thieme will look at multiple types of cells at the same time to understand the totality of how SRSF2 mutations lead to MDS.

Thieme’s interest in hematology started in seventh grade, when her brother was diagnosed with Hodgkin’s lymphoma. 

“He ended up receiving the standard of care treatment at that time, and he was young, and that worked,” Thieme said. “He is now in remission. I was inspired by the doctors that cared for him and scientists that discovered [the treatments] that cured him, and felt a desire to pay it back, because I have this amazing gift, which is my brother's life. And so if I could ever have some tiny part in doing that for someone else, then that would just make it all come full circle.”

Setty stressed the promise of Thieme’s research, as well as her creativity and independence in developing the project.

“This project exists because of Elana,” Setty said. “[She devised] this project with this specific long-read single-cell technology. That's completely opened up a new direction of thinking about how to understand splicing and how it is dysregulated in disease at the single cell level. It has opened up a completely new [research] direction for my lab. I feel incredibly proud of her, because she really has been the driver of this and I think this award is a terrific recognition of that.”

Understanding differential gene expression in infant leukemias

As a research technician at Fred Hutch from 2018 through 2022, Mendoza worked in the lab of Hans-Peter Kiem, MD, PhD, deputy director of the Translational Science and Therapeutics Division and holder of the Stephanus Family Endowed Chair for Cell and Gene Therapy.

While in the Kiem lab, Mendoza studied gene therapy in the context of blood disorders, helping to produce molecules for gene therapy experiments and receiving mentorship from Meera Srikanthan, MD, then a pediatric hematologist-oncologist also conducting research in the same lab. It was the start of an interest in hematology that would lead Mendoza to pursue his own PhD in the field.

Mendoza’s ASH project will tackle one of the most difficult leukemias to treat, lysine methyltransferase 2A-rearranged (KMT2A-r) leukemia. KMT2A is an enzyme that helps to control gene expression in blood cells by binding molecules known as methyl groups to exposed strands of DNA (one of several processes referred to collectively as epigenetic modifications). The methyl groups can either repel or attract gene promoters or repressors to the DNA, regulating the expression of specific genes. 

KMT2A rearrangements, in which the gene fuses improperly with nearby genes during cell division, are found in up to 80% of infant acute lymphoblastic leukemia, or ALL, as well as some cases of acute myeloblastic leukemia. Gene rearrangement can lead to mistakes in gene expression and blood cell differentiation (the process by which blood stem cells mature into the various lineages of cells seen in mature blood, including T cells and B cells). The mutation is considered to be particularly severe, especially in infant ALL.

“In childhood leukemia, we often see genes in the blood-forming stem cells break and recombine incorrectly prior to birth,” Mendoza said. “Over time, these mutations can transform normal stem cells into cancerous cells. We want to identify the early cellular changes that occur before obvious signs of disease appear.”

Mendoza will work with two professors in the Translational Science and Therapeutics Division, associate professor Brandon Hadland, MD, PhD, who also serves as a pediatric hematologist at Seattle Children’s, and assistant professor Scott Furlan, MD.

Mendoza will use CRISPR gene editing to introduce KMT2A-r mutations into human blood cells to observe the developmental origins of these leukemias. Using cells derived from donated human cord blood and induced pluripotent stem cell lines (iPS cells), Mendoza will observe the CRISPR-engineered KMT2A-r blood cells, both in cell culture and inside a model system. 

Using iPS cells allows researchers to simulate the embryonic development of immature blood cells, observing their development as they differentiate into the mature blood cells found in the human body.

“The ideal scenario is to use iPS cells to model blood development and introduce the [KMT2A-r] fusion at different time points, and then see how closely it mirrors human leukemia,” Mendoza explained. “That will give us some insight as to when in the process of embryonic development these fusions likely occur.”

Mendoza will observe how the cells grow and differentiate to study how leukemia begins.

“Mark is asking what happens during the silent, pre-leukemic phase, when only a tiny number of cells carry the KMT2A rearrangement, but the child still appears completely healthy,” Furlan said. “By engineering the exact KMT2A fusions we see in patients into human blood stem cells of fetal origin, and then following those cells over time with single cell genomics, Mark is mapping how these pre-leukemic cells gradually rewire their epigenetic programs and evolve into aggressive leukemia.”

While immunotherapy has increased the survival rate for KMT2A-r leukemia in recent years, there is still much to learn about how this mutation affects the epigenetic markers in affected blood cells. The long-term results of Mendoza’s research could include new ways to detect KMT2A rearrangements before a child develops leukemia, as well as new cellular targets for diseased cells that could respond to immunotherapy.

“Mark’s project has the potential to transform the way we approach pediatric leukemia,” Hadland said. “He wants to understand how pre-leukemic cells are potentially differentially susceptible to targeted therapies. If we could eradicate those pre-leukemic cells using less toxic treatments that prevent leukemia from developing in the first place, that kind of discovery could potentially be applied to other pediatric leukemias, many of which are the result of gene translocations that occur before birth.”