Early hematopoietic differentiation in acute lymphoblastic leukemia: The interplay between leukemia-initiating cells and abnormal bone marrow microenvironment

Abstract

By virtue of their self-renewal and tightly regulated multi-lineage differentiation properties, hematopoietic stem cells (HSCs) generate the whole blood system throughout postnatal life. During malignant hematological disorders, including acute leukemias, a number of intrinsic and extrinsic cues influence the hematopoietic differentiation pathway and cooperate to make aberrant cell fate decisions concomitant with cell transformation. The cellular origin of these disorders is a fundamental matter in question. In keeping with the hierarchical model of tumor evolution, a conspicuous and unique leukemic stem cell (LSC) population is most likely the foundation of acute and chronic myeloid leukemias. In contrast, all B-cell differentiation stages in acute lymphoblastic leukemia (ALL) function as leukemiainitiating cells (LICs), are endowed with primitive stem cell properties and are apparently responsible for the long-term maintenance of tumor growth within the bone marrow (BM) and for relapse of the disease following remission. Furthermore, LICs reveal the ability to create irregular BM microenvironments that may result in proinflammatory scenarios with a permissive role by allowing leukemic cell development at the expense of normal hematopoiesis. This chapter outlines the recent findings contributing to the understanding of malignant hematopoiesis through the biology of early stem and progenitor cells in the context of abnormal microenvironments within leukemic BM. By unraveling the role of leukemic precursor cells in the initiation of local inflammatory processes leading to hematopoietic instability, we may learn about additional mechanisms co-participating in the etiology and maintenance of this pathological condition.