Bone Marrow Collection for Induced Pluripotent Stem Cell Modeling of Acute Myeloid Leukemic Transformation of Myelodysplastic Syndromes
Tissue Collection for Disease Modeling
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.
The main objective of this proposal is to collect bone marrow samples from a total of 500 individuals with myelodysplastic syndromes (MDS), secondary acute myeloid leukemia (sAML) and also de novo AML and unaffected controls. MDS is a hematologic disorder that progresses to sAML in many patients, and both become increasingly prevalent in older individuals. The genetic, epigenetic and environmental causes of these disorders are poorly understood, not fully recapitulated in animal models, and suffer from insufficient availability of relevant human cells. The creation of human induced pluripotent stem cell (hiPSC) lines from patients with MDS and sAML would provide a renewable human cellular system for investigating the molecular basis of this disease that could potentially lead to the development of novel therapies. Impact and Significance - Although treatment options are few, reviewers questioned whether the targeted disease represents a compelling choice for an RFA program that focuses on prevalent diseases; reviewer enthusiasm was decreased because the disease occurs mostly in very elderly patients and is associated with substantial co-morbidities. - Several other banked sources of MDS and AML already exist for the study of normal and leukemic stem cells. It is unclear how the inclusion of the proposed patient population in this initiative would be unique and where significant overlaps would exist. - If hiPSC derived from bone marrow cells from the targeted patient population can be successfully employed to model the progression of MDS to sAML, this could lead to new important insights into disease mechanism and potential treatment options. Rationale - The applicant did not provide a compelling rationale for the numbers of samples needed to capture the disease spectrum and generate meaningful data. - Since each hiPSC line represents a single original source cell, it is not clear how a few hiPSC lines derived from one patient would capture the genetic heterogeneity of the disease. The applicant did not address this nor how mutations incurred during the reprogramming process would be distinguished from those present in the patients’ cells. Quality of the Proposed Protocols - Given the advanced age of the patient population and the discomfort of bone marrow biopsy, it is not clear why the applicants decided to obtain bone marrow derived cells rather than deriving the cells from mobilized peripheral blood. - Reviewers appreciated the fact that both bone marrow and blood have been collected from patients diagnosed with MDS and AML for quite some time, so elements of this proposal regarding the protocols for consent and logistics are already developed, well structured and of excellent quality. - Reviewers felt that consents, data management, and patient protection considerations all seem excellent. Feasibility - While the applicants provided quite detailed information regarding data management of patient samples and demographic and diagnostic information, reviewers found the number of proposed control lines to be excessive. - It is unclear whether generation of hiPSCs from AML cells is feasible, many cancers appear refractory to reprogramming and attempts to reprogram AML cells have failed to date. Budget - The budget is overall very modest and represents good value for proposed activities. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The applicant has an outstanding track record in the study of hematopoietic development and relevant clinical expertise. - The proposed team possesses the expertise, infrastructure and access to patients to ensure success in terms of recruitment.