About Christian Hurtz, PhD

B cell acute lymphoblastic leukemia is a malignancy that arises from B cells during early B cell development in the bone marrow. It is the most common type of cancer in children and often diagnosed in adults. Despite optimized chemotherapy regiments, personalized medicine approaches, and the development of immunotherapies, many children and adults cannot be cured from this disease. Malignant transformation of early B cells is facilitated by oncogenic fusions and other genetic mutations, which results in the development of multiple different subtypes of acute lymphoblastic leukemia. Patients diagnosed with Philadelphia chromosome-like (Ph-like) or KMT2A-rearranged (KMT2A-R) leukemia have a poor prognosis and a significantly worse clinical outcome compared to most other leukemia subtypes.

The goal of the Hurtz laboratory is to enhance the understanding of the pathogenesis of these high-risk leukemia subtypes and to identify new treatment strategies to improve the clinical outcome of children and adults. Using B cells and B cell-derived leukemia model systems, we aim to develop lineage-specific treatment strategies that are effective at eradicating cancer cells but not harmful to healthy cells. To identify novel targets, we combine molecular biology and bioinformatic approaches and perform translational mouse in vivo studies to validate our findings.

Ongoing projects in our laboratory include:

1) New vulnerabilities in Ph-like ALL

Ph-like acute lymphoblastic leukemia (ALL) is a disease defined by the presence of a specific gene expression profile rather than by the presence of a specific oncogene. Among the most common oncogenic mutations found within the subset of Ph-like ALL are the CRLF2-rearrangements (CRLF2-R). CRLF2-R constitutively activate STAT5 signaling via JAK2. In addition to STAT5, other signaling molecules including AKT and ERK are also constitutively activated. Our results demonstrate that genetic deletion of CRLF2-R or JAK2 inhibition inhibits STAT5 signaling, but only marginally downregulates AKT and ERK signaling, suggesting an oncogene independent regulation of these molecules. Furthermore, JAK2 inhibition results in the accumulation of DNA damage without induction of apoptosis. During B cell differentiation V(D)J recombination is initiated by the downregulation of STAT5 signaling. V(D)J recombination is a process that allows early B cells to rearrange their B-cell receptor heavy and light chains. During this process the RAG1/2 enzyme complex cuts DNA causing temporary DNA damage, which ultimately gets repaired and B cells are protected from apoptosis during this process. Our results indicate that the mechanism of V(D)J recombination and consequent induction of DNA damage is a molecular conserved mechanism between early B cells and Ph-like ALL cells. However, it also indicates that JAK2/STAT5 inhibition may increase the resistance of Ph-like ALL to therapy, given that cells are protected from apoptosis during V(D)J recombination.

The goals of this project are:

1) Identify molecules that mediate the reactivation of AKT and ERK signaling in Ph-like ALL cells, determine the molecular mechanism of reactivation, and perform translational in vivo studies to validate the effectiveness of combinatorial treatment strategies.

2) Determine if inhibition of DNA repair molecules sensitizes Ph-like ALL cells to JAK2 inhibition via molecular defined experiments using genetically modified mouse models and pharmacologic in vivo validation using patient derived xenograft (PDX) samples.


2) Signaling hyperactivation and negative selection in KMT2A-R ALL

KMT2A-rearranged (KMT2A-R) leukemia is a high-risk disease with a frequency of about 70% in infants and about 10% in older children and adults with leukemia. KMT2A is a well-studied histone methyltransferase involved in epigenetic and transcriptional regulation. Identifying inhibitors to suppress the epigenetic or transcriptional activity of KMT2A has been challenging and mostly unsuccessful clinically. Performing kinome wide-CRISPR screens we identified that KMT2A-R ALL cells are uniquely sensitive to DYRK1A deletion. Mechanistically, our results indicate that DYRK1A negatively regulates ERK phosphorylation and pharmacologic inhibition of DYRK1A results in ERK hyperphosphorylation and consequent cell death in KMT2A-R ALL but not KMT2A-R acute myeloid leukemia. Combining DYRK1A inhibitors with RAS downstream inhibitors antagonistically rescues KMT2A-R ALL cells from cell death, indicating that the hyperphosphorylation of ERK specifically mediates the induction of cell death. B cells with increased B cell receptor signaling activation are negatively selected during B cell differentiation to prevent autoreactive B cells from harming healthy cells. Our data indicates that inhibition of DYRK1A and consequent induction of ERK hyperphosphorylation mimics an autoreactive B cell receptor and represents a novel avenue to treat KMT2A-R leukemia compared to the current treatment strategies that aim to downregulate kinase activity.

The goals of this project are: 

1) Demonstrate that DYRK1A is an important gatekeeper molecule that regulates B cell receptor signaling strength via ERK phosphorylation to prevent negative selection and elucidate the potential benefit of pharmacologic DYRK1A inhibition in vivo using KMT2A-R leukemia PDX models.

2) Develop a new treatment approach to genetically delete DYRK1A in vivo to prevent inhibitor mediated toxic side effects.

Recent publications on these topics:       
Hurtz C et al., Oncogene-independent BCR-like Signaling Adaptation Confers Drug Resistance in Ph-like ALL. J Clin Invest. 2020. PMID: 32191635

Tasian SK and Hurtz C et al., High Incidence of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia (Ph-like ALL) in Older Adults with B-ALL. Leukemia. 2017. PMID: 27932787

Geng H and Hurtz C et al., Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia, Cancer Cell 2015 PMID:25759025

Hurtz C and Chan LN et al., Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes & Development 2019 PMID:31395741