Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia.

John Anto Pulikkan,Lucio Hernán Castilla

doi:10.3389/fonc.2018.00129

John Anto Pulikkan, Lucio Hernán Castilla

Open Access

https://doi.org/10.3389/fonc.2018.00129

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Abstract

Acute myeloid leukemia (AML) is a collection of hematologic malignancies with specific driver mutations that direct the pathology of the disease. The understanding of the origin and function of these mutations at early stages of transformation is critical to understand the etiology of the disease and for the design of effective therapies. The chromosome inversion inv(16) is thought to arise as a founding mutation in a hematopoietic stem cell (HSC) to produce preleukemic HSCs (preL-HSCs) with myeloid bias and differentiation block, and predisposed to AML. Studies in mice and human AML cells have established that inv(16) AML follows a clonal evolution model, in which preL-HSCs expressing the fusion protein CBFβ–SMMHC persist asymptomatic in the bone marrow. The emerging leukemia-initiating cells (LICs) are composed by the inv(16) and a heterogeneous set of mutations. In this review, we will discuss the current understanding of inv(16) preleukemia development, and the function of CBFβ–SMMHC related to preleukemia progression and LIC activity. We also discuss important open mechanistic questions in the etiology of inv(16) AML.

Highlights

The core-binding factor (CBF) transcription factor has critical roles in hematopoietic stem cell (HSC) maintenance and differentiation by regulating expression of genes associated with cell fate decisions and proliferation in lymphoid and myeloid compartments [1]
The finding that mutations in genes associated with epigenetic complexes, frequently mutated in other Acute myeloid leukemia (AML), are practically absent in inv[16] AML suggests that CBFβ–SMMHC function may deregulate chromatin dynamics
Future studies are endowed to demonstrate whether preLHSCs can produce preleukemia initiating cells in inv[16] AML (Figure 2)

Summary

Introduction

The core-binding factor (CBF) transcription factor has critical roles in hematopoietic stem cell (HSC) maintenance and differentiation by regulating expression of genes associated with cell fate decisions and proliferation in lymphoid and myeloid compartments [1]. The preleukemic HSCs (preL-HSCs) can be considered as HSCs with inv[16] as a founding mutation that generate a clonal expansion of myeloid progenitor cells primed for leukemia [15]. A later study using Cbfb+/MYH11d179-221 knock-in mice expressing CBFβ– SMMHC lacking the HABD established that HABD regulates myeloid differentiation induced by CBFβ–SMMHC but it may inhibit leukemia by altering the LIC pool [22].

Results

Conclusion