Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay

Abstract

The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e. dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event; however, disease progression still occurs in those patients who are refractory, not compliant with TKI therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCR-ABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression. Indeed, it seems that bone marrow (BM) microenvironment-generated signals and cell autonomous BCR-ABL1 kinase-independent genetic and epigenetic alterations all contribute to: i. persistence of a quiescent leukemic stem cell (LSC) reservoir, ii. innate or acquired resistance to TKIs, and iii. progression into the fatal blast crisis stage. Herein, we review the intricate leukemic network in which aberrant, but finely tuned, survival, mitogenic and self-renewal signals are generated by leukemic progenitors, stromal cells, immune cells and metabolic microenvironmental conditions (e.g. hypoxia) to promote LSC maintenance and blastic transformation.

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

“…In recent decades, a high number of biological studies have been done to elucidate the molecular mechanisms of CML pathogenesis and progression [ 16 , 17 , 18 ]. The results of these studies were fundamental to understand how and why the p210 tyrosine kinase protein is able to drive the leukemic transformation of Ph+ hematopoietic progenitors by altering cell proliferation, apoptosis, adhesion and inducing genomic instability [ 1 , 2 ].…”

Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation

“…CML is a myeloproliferative disorder of hematopoietic stem cells and accounts for 20% of all leukemias affecting adults (38,39). CML is caused by reciprocal translocation between the long arms of chromosome 22 and 9 that results in the formation of the chimeric Bcr-Abl (break-point cluster region-abelson) oncogene.…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…However, we hypothesize that various CML myeloid progenitors and more differentiated myeloid CML cells in chronic phase disease are involved in TNT formation in vivo under TKI and IFNα therapy, particularly since the CML cells interacts with a wide repertoire of stromal and host cells at various anatomical locations. 11,84 Chronic myeloid leukemia with its pathognomonic BCR-ABL1 fusion protein is one of several myeloid neoplastic diseases that originate from hematopoietic stem cells, 85,86 and in which the malignant cell has a close relation to mesenchymal support cells in the bone marrow. TNTs are proposed as one mechanism of interaction between mesenchymal stromal cells and leukemic cells in the leukemic stem cell niche.…”

“…5 Imatinib was the first of a series of BCR-ABL1-targeted drugs used in treatment of CML patients, and these inhibitors vary based on potency, efficiency on mutated ABL1 and have different adverse effect profiles. [6][7][8] The role of BCR-ABL1 in microenvironment dependent cellular communication is less understood [9][10][11] particularly in the context of the efficient therapies with small molecule kinase inhibitors. [12][13][14] It is well established that the tumor microenvironment and its cell-to-cell interactions play a pivotal role in the outcome of cancer therapy.…”