Differentiation of leukemic blasts is not completely blocked in acute myeloid leukemia

Abstract

Hematopoiesis, the formation of blood cells, involves the hierarchical differentiation of immature blast cells into mature, functional cell types and lineages of the immune system. Hematopoietic stem cells precisely regulate self-renewal versus differentiation to balance the production of blood cells and maintenance of the stem cell pool. The canonical view of acute myeloid leukemia (AML) is that it results from a combination of molecular events in a hematopoietic stem cell that block differentiation and drive proliferation. These events result in the accumulation of primitive hematopoietic blast cells in the blood and bone marrow. We used mathematical modeling to determine the impact of varying differentiation rates on myeloblastic accumulation. Our model shows that, instead of the commonly held belief that AML results from a complete block of differentiation of the hematopoietic stem cell, even a slight skewing of the fraction of cells that differentiate would produce an accumulation of blasts. We confirmed this model by interphase fluorescent in situ hybridization (FISH) and sequencing of purified cell populations from patients with AML, which showed that different leukemia-causing molecular abnormalities typically thought to block differentiation were consistently present in mature myeloid cells such as neutrophils and monocytes at similar levels to those in immature myeloid cells. These findings suggest reduced or skewed, rather than blocked, differentiation is responsible for the development of AML. Approaches that restore normal regulation of hematopoiesis could be effective treatment strategies.

Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells

“…For example, recent studies indicated that within certain immunophenotypic fractions such as CD34 + /CD38 -, other factors such as reactive oxygen species content are able to identify which cells are functional LSCs (18,19). Furthermore, mathematical modelling studies of leukaemogenesis have indicated that mature myeloid cells can often have the same genotype as leukaemic blasts, highlighting that differentiation of leukaemic blasts is not completely blocked in the disease (20). A comprehensive single-cell sequencing study by Bernstein et al has indicated intra-tumoural heterogeneity of malignant AML cells and uncovered that some undefined phenotypic markers may be expressed by both malignant and normal cells (21).…”

A Review of Molecular and Genetic Diagnostics of Myeloid Malignancies with Emphasis on Diagnostics in Bosnia and Herzegovina

“…It arises due to genetic changes in the DNA of myeloid precursors. It is characterized by an obstruction in differentiation and a continuous division of immature myeloid cells, more precisely leukemic blasts, which impair normal hematopoiesis (20). AML primarily forms in the bone marrow, but in most cases, blasts are also found within the peripheral blood.…”

Hilab system, a new point-of-care hematology analyzer supported by the Internet of Things and Artificial Intelligence

“…For providing important information about the general patient’s health, the complete blood count (CBC) is one of the most ordered tests by physicians around the world. Besides being used as a screening, it is essential for the diagnosis and evolutionary control of infectious diseases, medical emergencies, surgeries, traumatology, in addition to chemotherapy and radiotherapy accompaniment 1 and, therefore, considered an essential diagnostic tool by the World Health Organization 2 . The main parameters evaluated in CBC are the total count of red blood cells (RBC), platelets (PLT), and white blood cells (WBC).…”