University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Hematopoietic Malignancies

The Hematopoietic Malignancies Program includes 25 members from 9 academic departments from the UCSF Schools of Medicine and Pharmacy. The overarching goals of the Program are to (1) develop more effective and less toxic therapeutics for hematopoietic cancers that are based on an increased understanding of molecules that regulate the growth, differentiation, and death of these cells; (2) characterize the functions of genes and proteins that are critical for the normal growth of immature and lineage-committed hematopoietic cells; (3) develop and exploit animal models for biologic and preclinical therapeutic studies; (4) investigate the genetic and environmental causes of hematologic cancers; (5) support the career development of young scientists; and (6) educate trainees, health care professionals, patients, and the public about leukemia, lymphoma, and myeloma.

The Hematopoietic Malignancies Program conducts research under four themes:

  • Theme 1: The Biology of Hematopoietic Stem Cell Transplantation (HSCT)
  • Theme 2: Signal Transduction in Myeloid Cells, Myeloid Leukemogenesis, and Targeted Therapeutics
  • Theme 3: Mechanisms of Lymphoid Growth Control, Transformation, and Response to Therapeutics
  • Theme 4: Clinical, Translational, and Population Sciences Research in Lymphoid Malignancies

Several principles underlie this multi-disciplinary program including the fundamental premise that investigating how normal hematopoietic cells regulate growth, differentiation, and death; and these principles are integral to understanding how these processes are perturbed in cancer. Furthermore, laboratory studies of primary leukemia, lymphoma, and myeloma specimens can provide complementary insights into mechanisms of hematopoietic cell growth and leukemogenesis. Studies of human hematologic cancer specimens and in accurate mouse models are integral for translating research insights into innovative preclinical and clinical trials that are essential for improving the care of patients afflicted with cancer. Applying this philosophy to leukemia, lymphoma, and myeloma has resulted in a program that includes a diverse and highly interactive group of clinical, translational, population sciences, and basic investigators who utilize a variety of experimental methods to conduct studies in normal and malignant hematopoiesis.

Characterizing how normal physiologic processes are perturbed in hematologic malignancies will provide a scientific foundation for rational new strategies to diagnose, prevent, and treat these cancers. Because the molecular alterations that contribute to leukemia, lymphoma, and myeloma are relatively well understood, these malignancies also provide exceptional opportunities to develop animal models for testing new treatment strategies. UCSF investigators have generated a number of relevant mouse models, which are being used to elucidate targets for rational therapeutic intervention, to perform translational preclinical trials, and to characterize mechanisms of drug response and resistance.

The Program has established a highly interactive interdisciplinary approach that includes research efforts directed at gene discovery; modeling leukemia, lymphoma, and myeloma-associated genetic lesions in the mouse; characterizing signal transduction pathways that are crucial for cellular growth control and are perturbed in hematologic cancers; testing experimental therapeutics with molecular analysis to ascertain mechanisms of drug action and drug resistance; and defining environmental risk factors that contribute to the development of hematologic cancers. The Program is built upon extraordinary institutional strengths in basic and population sciences; outstanding clinical programs for the care of patients with leukemia, lymphoma, and myeloma; and a tradition of cross-disciplinary collaborations in scientific investigations.

 

 

> The Biology of Hematopoietic Stem Cell Transplantation (HSCT)
> Signal Transduction in Myeloid Cells, Myeloid Leukemogenesis, and Targeted Therapeutics
> Mechanisms of Lymphoid Growth Control, Transformation, and Response to Therapeutics
> Clinical, Translational, and Population Sciences Research in Lymphoid Malignancies


Theme 1: The Biology of Hematopoietic Stem Cell Transplantation (HSCT)

Dr. Emmanuelle Passegue’s lab demonstrated that replication stress is a potent driver of functional decline in aging HSCs, and identified a deficit in MCM DNA helicase components as the underlying mechanism for the impaired replication of old HSCs (Flach et al., Nature, 2014).

Theme 2: Signal Transduction in Myeloid Cells, Myeloid Leukemogenesis, and Targeted Therapeutics

Dr. Kevin Shannon’s group generated more than 40 drug-resistant primary T-ALLs through treatment of mice with the PI3K inhibitor GDC-0941 alone or in combination with a MEK inhibitor, and found that these leukemias frequently down-regulated activated Notch1/Myc signaling, which led the group to discover a novel negative feedback loop between the Notch and PI3K pathways as the mechanistic basis for this unexpected observation (Dail et al., Nature, 2014).

Dr. Neil Shah’s lab reported a co-crystal structure of the FLT3 kinase domain with quizartinib, and performed preclinical and translational studies with the next generational investigational FLT3 inhibitor PLX3397 (pexidartinib) that demonstrated the ability of this agent to retain activity against the problematic TKI-resistant FLT3 gatekeeper mutant F691L (Smith et al., Cancer Discovery, 2015).

Theme 3: Mechanisms of Lymphoid Growth Control, Transformation, and Response to Therapeutics

Dr. Davide Ruggero’s lab found that levels of nucleotide metabolites are particularly sensitive to the protein synthesis output of Myc-overexpressing cells, and through a candidate screen, identified a singular translationally regulated target gene, PRPS2, that serves as the rate-limiting enzyme of nucleotide production in cancer cells driven by Myc hyperactivation. When crossed to a Myc-driven mouse model of lymphoma, knockout of the PRPS2 locus displayed a dramatic extension of disease-free survival, highlighting the critical role this enzyme plays in cancer cell homeostasis (Cunningham et al., Cell, 2014).

Dr. Jason Cyster and colleagues determined that a pathway dependent upon the Gα13-coupled receptor exerts dual actions in suppressing growth and blocking dissemination of germinal center B cells, and is frequently disrupted in germinal center B-cell-derived lymphoma (Muppidi et al., Nature, 2014).

Dr. Markus Müschen, in collaboration with Drs. Mignon Loh and Clifford Lowell, showed that an incremental increase of Syk tyrosine kinase activity engages a deletional checkpoint for removal of self-reactive B cells and selectively kills ALL cells, and that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signaling flux through recruitment of the inhibitory phosphatases Ptpn6 (Chen et al., Nature, 2015).

Theme 4: Clinical, Translational, and Population Sciences Research in Lymphoid Malignancies

Dr. Thomas Martin collaborated with Drs. Andrew Leavitt, Lloyd Damon, Charalambos Andreadis, Weiyun Ai, and Lawrence Kaplan on a multicenter analysis that found evidence that hematopoietic recovery is delayed following autologous stem cell transplantation in patients with acute promyelocytic leukemia who are treated with arsenic trioxide (Mannis et al., Bone Marrow Transplant, 2015).