Lam Lab Research

About the Research 

Dr. Lam’s laboratory investigates how leukemia and leukemia stem cells survive oncogenic and treatment-related stress by relying on proteostasis, a network of interconnected pathways that control protein synthesis, folding, and degradation. We focus on how leukemia cells maintain protein quality control under stress and how these adaptations create actionable therapeutic vulnerabilities.

A central recent discovery from our group is that proteasome inhibitors (highly effective in multiple myeloma) are comparatively ineffective in acute myeloid leukemia (AML). Proteasome inhibition often fails to disrupt proteostasis in AML because AML cells do not accumulate unfolded proteins to the same extent that triggers lethal stress responses in myeloma. Instead, AML cells rapidly activate compensatory proteostasis programs, including HSF1-mediated heat-shock responses and increased autophagic flux, which together prevent proteotoxic collapse and promote drug tolerance.

Importantly, our work demonstrates that disabling these compensatory pathways can sensitize AML to proteostasis disruption via proteasome inhibition. Genetic inactivation of HSF1 sensitizes AML cells to proteasome inhibition, leading to unfolded protein accumulation, activation of PERK-mediated terminal integrated stress response (ISR), profound suppression of protein synthesis, impaired proliferation/survival, and slowed disease progression in vivo. Similarly, combined autophagy and proteasome inhibition synergistically suppresses AML growth, reduces leukemia burden, and extends survival in preclinical models. This dual targeting preferentially suppresses protein synthesis and induces apoptosis in primary patient AML samples, supporting a potential therapeutic window for translation. Notably, we also found that terminal ISR engaged by combined autophagy and proteasome inhibition can be PKR-dependent. These studies provide an initial framework of how to target proteostasis in AML and reveal that disabling proteostasis can be a potent therapeutic strategy.

Looking forward, we aim to map how proteostasis wiring differs across AML and its various genetic subtypes, as well as in other blood malignancies. Ultimately, our lab’s mission is to identify proteostasis vulnerabilities in leukemia and cancer stem cells, and turn them into precision treatment strategies that prevent relapse and improve long term outcomes for patients.