Abstract Acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are aggressive forms of blood cancer that impair normal hematopoiesis and are typically associated with bone marrow (BM) failure, reflected by peripheral blood pancytopenia. While BM failure is thought to be mediated by the loss of hematopoietic stem and progenitor cells (HSPCs) due to leukemic expansion, with leukemic cells “crowding out” normal HSPCs, the mechanisms underlying this process remain unclear. To elucidate these mechanisms, we examined the effects of AML or ALL on residual normal or wild type (WT) hematopoiesis. The 961C cell line is an AML cell line derived from a NUP98-PH23 (NP23) transgenic mouse, and the T259 cell line is a B cell precursor ALL (BCP ALL) cell line also derived from an NP23 mouse. AML and BCP ALL were generated by transplantation of 961C or T259 cell lines into congenic recipients without cytotoxic conditioning. The use of congenic mice allowed engraftment of immunocompetent mice, and the lack of cytotoxic conditioning prevented damage to the BM microenvironment. Mice with AML demonstrated severe anemia, thrombocytopenia, and depletion of HSPCs, along with a marked reduction of total BM cellularity (WT + AML cells), suggesting that BM suppression was not due to a physical “crowding” mechanism. Instead, BM suppression in the absence of BM replacement with myeloblasts suggested that hematopoiesis may be inhibited by a factor secreted by the AML blasts. The inflammatory cytokines TNF-A and IL-6 were markedly increased in the peripheral blood of mice with AML, suggesting these were candidates for a factor responsible for decreased cellularity and pancytopenia. In contrast, mice with BCP ALL demonstrated normal hemoglobin and leukocyte counts, even with significant ALL engraftment. The loss of WT hematopoietic cells in the BM was equivalent to the gain of leukemic cells in the BM, and the total number of leukemic cells in mice with BCP ALL was 14-fold higher than the number of leukemic cells in mice with AML. Of note, the spleen of mice with BCP ALL displayed a 100x increase in WT HSPCs compared to non-transplanted mice with healthy BM. These findings suggest that BCP ALL depletes WT HSPCs in the BM through a physical expansion mechanism. WT splenic HSPCs from mice with AML were shown to have normal numbers of functional hematopoietic stem cells via a limiting dilution assay. In addition, WT HSPCs harvested from mice with BCP ALL generated similar numbers and types of colonies in vitro compared to WT HSPC harvested from non-leukemic mice. Both experiments suggest that neither BCP ALL nor AML induced a permanent change in the functionality of WT HSPCs. In conclusion, our results suggest that AML induces BM failure independent of leukemic burden, possibly via a secreted cytokine, whereas BCP ALL induces BM failure through physical expansion that replaces WT HSPCS with leukemic cells. Citation Format: Ryan Matthew Bertoli, Peter D. Aplan, Yang Jo Chung. Mechanism for bone marrow failure differs between acute myeloid and lymphoid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3664.