Myelodysplastic syndromes (MDS) represent a heterogeneous group of pre-leukemic disorders, characterized by ineffective hematopoiesis and abnormal blood cell development in one or more lineages. Aging of the general population and increased chemotherapy use have contributed to increasing MDS prevalence and represent a growing health care economic burden that is expected to continue to increase over the next several decades. Of an estimated 232,000 individuals living with MDS in the US, 30% of patients progress to sAML with a 5-year survival rate of only 25%. Notably, there is no curative treatment and there are no approved therapies for patients with epigenetic modifier resistant disease. The new California-based MDS, AML and aged bone marrow biobank proposed here will be provide a tool for elucidating key age-related changes in stem cell biology that set the stage for malignant transformation. The bank will be developed specifically for the use of these tissue samples for the generation of human induced pluripotent stem cells (hiPSC) that can be used to study both genetic and epigenetic mechanisms that fuel age-related stem cell changes that lead to MDS initiation and AML transformation. Generation of human MDS and AML stem cells from bone marrow-derived hiPSC would provide an experimentally amenable platform to expedite the development of sensitive diagnostic techniques to predict disease progression and to develop potentially curative cancer stem cell targeted therapies.
Statement of Benefit to California:
Affecting an estimated 23,000 Californians, myelodysplastic syndromes (MDS) represent genetically complex age-related stem cell derived disorders typified by ineffective blood cell development and a propensity to transform to therapeutically resistant secondary acute myeloid leukemia (sAML). Aging of the population and increased survival following chemotherapy and radiation therapy for cancer has resulted in an increasing prevalence of MDS and sAML, with a paucity of effective therapies thereby representing a growing healthcare economic burden. This project aims to collect human bone marrow stem cells from patients suffering from MDS and acute myeloid leukemia (AML) along with normal subjects. California stem cell research harbors tremendous potential for shedding light on the disease initiating events that skew blood cell differentiation versus events that promote self-renewal and thus, leukemic transformation. Moreover, future studies of the hiPSC lines generated in the context of this initiative will pave the way towards a more comprehensive understanding of early stem cell fate decisions and genetic abnormalities driving the development of MDS and AML compared with normal aged controls. The hiPSC lines generated in the context of this grant will be made available to California researchers, and this will speed the delivery of innovative therapies for Californians with hematologic disorders, bringing both significant economic and public health benefits to the state.