Abstract 3196: Focus on adipocytes in the growth, resistance, and lethality of extramedullary leukemic tumors could transform our approach to curing leukemia
Authors: Cunningham Isabel , Goldman James E. 
Published: June 2022

Abstract
We investigated whether the proposed role of adipocytes in driving solid cancers could apply to breast tumors formed of leukemia cells. This could explain the desmoplastic collagen deposition, metastasis, resistance, and lethality of these tumors that we previously reported. All 290 published cases of breast tumors composed of acute myeloid leukemia (AML) cells were reviewed and extended survivals were solicited from authors. RNA sequencing compared 11 AML breast samples to normal breast. Histology revealed invasion of adipose tissue by AML cells, many of which resided at the adipocyte periphery, accompanied by a shrinkage of adipocytes and the accumulation of collagen and elongated fibroblastic-like cells. Both lymphocytes and macrophages accompanied the infiltration. RNA sequencing showed deregulation of numerous adipose genes, including adiponectin, leptin, FABP4, COL6A3, CD36, and PPARγ, as reported in co-culture studies of breast and other solid cancer cells with adipocytes. Analysis of 210 clinical cases with available followup data revealed a survival benefit of tumor excision and/or irradiation in combination with systemic leukemic agents compared to systemic treatment alone. Two-year survival was achieved with excision +/- RT + systemic agents in 35/88 (40%), with RT + systemic agents in 12/38 (32%) and in 12/84 (14%) given systemic treatment alone. Five-year survival was achieved in 19%, 11%, and 2%, respectively. Eleven patients given surgery +/- RT with systemic treatments survived 10+ to 19+ years. This study reveals for the first time that removal/ablation of leukemic tumors and microenvironment can result in prolonged survival and potentially cure. Agents designed to treat marrow leukemia are ineffective in eradicating cells that have adopted solid tumor phenotype. The observed histologic features and clinical behavior of leukemic breast tumors could result from leukemic cell crosstalk with adipocytes, as reported in solid breast and other cancers. Invasion of fat is correlated with poor prognosis in many cancers. It is very likely that our findings also apply to hematologic tumors in other organs, as most contain or are near adipose tissue. Treating to cure extramedullary leukemia using combined excision/RT and systemic therapy requires confirming that the tumor is isolated and no occult tumors are present. This was not documented in most published cases. Only 10% of reported patients had PET/CT scans, so greater success is expected when body scans are routinely used in staging leukemia, as has been routine in every other cancer for decades. Until pharmacologic agents to interrupt malignant cell-adipocyte crosstalk are available, direct treatment of hematologic tumor after total body scan should be a new standard of care.
Citation Format: Isabel Cunningham, James E. Goldman. Focus on adipocytes in the growth, resistance, and lethality of extramedullary leukemic tumors could transform our approach to curing leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3196.