A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy

Abstract

The BCL-2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine/pyrimidine metabolism, and selective sensitivity to cladribine. Critically, in some instances m-LSC and p-LSC subtypes can co-reside in the same AML patient and simultaneously contribute to overall tumor complexity. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlights the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens.

Interpreting single-cell messages in normal and aberrant hematopoiesis with the Cell Marker Accordion

“…A significant increase is observed in AML patients with respect to HDs. (E) Accordion annotation of human bone marrow cells from healthy donors (HD) at diagnosis and relapse time point 57 . (F) Identification of leukemia stem cells (LSCs) with the Accordion Disease.…”

“…These results are consistent with the lineage-specific alterations induced by U2AF1 S34F, with impaired erythroid and granulomonocytic differentiation 39,68 . Moreover, these results suggest that the U2AF1 S34F mutation drives a monocytic phenotype associated with poor clinical outcomes 57 .…”

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

“…Despite the success of this regimen, approximately 30% of patients do not respond upfront and the majority of patients who initially achieve a response ultimately relapse on therapy [1,3,4]. Notably, while venetoclaxbased regimens are able to directly target some LSCs [2], resistant LSCs either co-reside or evolve from sensitive LSCs [5,6] and confer resistance. Consequently, there is an urgent need to develop therapeutic strategies to target venetoclax-resistant LSCs.…”

“…6 cells to avoid potential graft-versus-host disease. Per mouse, 2 × 10 6 cells in 0.1 mL saline were tail vein injected; there were 8 to 16 mice per experiment group.…”

Toward an improved understanding of hypomethylating agent and venetoclax therapies

“…It is increasingly apparent that the overlap of signaling mutations (FLT3-ITD, KRAS, NRAS, and PTPN11) with monocytic phenotypes and other anti-apoptotic family protein resistance patterns in HMA-VEN-treated patients are important and incredibly challenging relationships to dissect, and additional work with larger validation cohorts will clearly be required. 10,11 Notably, 14% of patients (n = 41) in the Gangat analysis transitioned to allogeneic stem cell transplant (SCT), and SCT consolidation was associated with improved outcomes in all three Mayo risk groups, with a 3-year OS in transplanted patients of 66%. This impressive statistic is also similar to previous publications, such as a median OS of 2.5 years in patients receiving allogeneic SCT primarily from the original Phase 1b HMA + Venetoclax trial 12 and further reinforces that transplants should be considered in all appropriate patients to improve the chance for curative therapy, regardless of baseline risk.…”