講師１ 東京大学医科学研究所 先端医療研究センター 細胞療法分野・准教授
講師２ Professor and Chairman, Translational Hematology and Oncology Department Taussig Cancer Center, Cleveland Clinic Cleveland, Ohio
1．Therapy-resistant leukemia stem cells in acute myeloid leukemia
2．Early clonal events determine hierarchical progression in myeloid neoplasia: impact on resulting morphologic features.
1.The leukemia stem cell (LSC) model has received considerable attention in the past 20 years with the identification of rare cell populations expressing stem cell markers in leukemia cell populations. LSCs are thought to be responsible for leukemia initiation, recurrence, and drug resistance, thus being regarded as excellent targets for developing curative therapies. However, characters of LSCs that are resistant to specific types of therapies have not been fully understood. Using a mouse model for myeloid leukemia, we found that a p53-Mdm2 interaction inhibitor (DS-5272) showed the robust anti-leukemia effect against MLL-AF9 leukemia in vivo. Nevertheless, all mice eventually developed leukemia, indicating the existence of therapy-resistant LSCs. These LSCs were relatively enriched within the bone marrow (BM) endosteal region where osteoblasts reside, and expressed higher levels of Hif1 and PD-L1. The antileukemia effect of DS-5272 was markedly attenuated in immunodeficient mice, indicating the critical impact of systemic immune responses that drive p53-mediated leukemia suppression. Furthermore, inhibition of Hif1 and PD-L1 sensitized leukemia cells to DS-5272. Our study showed the potent activity of a p53-MDM2 interaction inhibitor against MLL-fusion leukemia, which is further augmented by antitumor immunity.
2.Myelodysplastic syndromes (MDS) arise in the elderly through stepwise acquisitions of many possible somatic mutations. The clinical diversity of this disease reflects heterogeneity of the resulting clonal architecture. Through analysis of 1,809 MDS patients (of which over 150 were studied serially), we demonstrate using specifically developed bio-statistical/analytic pipeline that the ancestral hits are mutually exclusive and defining of subsequent evolution not via a random, but rather preferential acquisition of specific secondary mutations. We have also objectively digitalized major morphologic features including the presence of various forms of dysplasia, cytopenia and myeloproliferative features (monocytosis, fibrosis increased megakaryocytes) obtained through a uniform unbiased and blinded pathologic evaluation. These features have been correlated with the presence of specific mutations and common mutational combinations. A number of important relationships between specific morphologic profiles and mutation combinations have been uncovered allowing to determine predictive value of morphologic configurations with regard to certain genotypes and vice versa. Similarly, our analysis revealed a convergence of molecular pathways steaming from distinct lesions towards common shared morphology. We also show that mutations in some genes exert different effects of the clinical features depending on their position in the clonal hierarchy. The latency between ancestral and secondary hits can be long, as evidenced by their presence in a prevalent condition known as clonal hematopoieisis of indeterminate potential (CHIP). Separating ancestral and secondary hits in MDS patients and comparing frequencies of mutations identified in meta-analysis of CHIP enabled us to speculate molecular and clinical characteristics of CHIP-related MDS and contrast them to MDS arising as de novo disease characterized by very penetrant mutations with a shorter latency to manifest disease. Patients with CHIP-related MDS had dominant TET2, DNMT3A and ASXL1 mutations, and overall higher mutational burden, were more elderly, exhibited less -7/del(7q) and complex karyotype, and showed better prognosis compared to those in CHIP-unrelated de novo MDS. In sum, we conclude that MDS patients can be broadly partitioned into pathogenically distinct CHIP-related vs. –unrelated MDS forms. Certain mutational configurations create morphologic configurations with subclonal hits further shaping the resultant morphology. Distinction of MDS by founder lesions and the presence of sweeping subclonal hits has wide-ranging therapeutic consequences.