Chronic Myeloid Leukemia Stem Cells

Abstract

Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell-specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.

Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy

“…In vitro data have shown that TKI therapy is unable to eliminate LSCs, which is at least partly due to BCR-ABL1-independent survival of the quiescent cells (4,6,9,10,(27)(28)(29)(30). In concordance with the in vitro data, it has been shown that in almost all patients in sustained complete molecular response on the RNA level after discontinuation of imatinib, the BCR-ABL1 rearrangement DNA can still be detected in genomic DNA or in selected CD34 þ CD38 À cells (10,31).…”

Chronic myeloid leukemia: mechanisms of blastic transformation

“…In support of this suggestion, expression studies revealed that BCR-ABL1 dramatically perturbs the CML transcriptome (31), resulting in altered expression of genes, some of which (e.g., PRAME, MZF1, EVI-1, WT1, and JUN-B) might play a role in BP (19,(32)(33)(34). Nonetheless, the posttranscriptional, translational, and posttranslational effects of high BCR-ABL1 levels result in the constitutive activation of factors with reported mitogenic, antiapoptotic, and antidifferentiation activity (e.g., MAPK ERK1/2 , MYC, JAK2, YES-1, LYN, hnRNP-E2, MDM2, STAT5, BMI-1, and BCL-2) and inhibition of major key regulators of cellular processes, such as those regulated by the tumor suppressors p53, CCAAT/enhancer binding protein-α (C/EBPα), and PP2A (19,29,35). Interestingly, a signature based on six genes (NOB1, DDX47, IGSF2, LTB4R, SCARB1, and SLC25A3) was recently found to accurately discriminate early from late CP, CP from AP, and CP from BP (36); however, the biological role of these genes in disease progression is still unknown.…”

Stem Cells in Acute Lymphoblastic Leukaemia

“…41 There is also evidence that HSCs are involved in the pathogenesis of some leukaemias, including chronic myeloid and lymphoblastic leukaemias. 42,43 However, the CSC hypothesis does not preclude the possibility that transformation occurs in more differentiated cell types, which then re-initiate stemness pathways. Lymphoid cells retain the ability to clonally expand even after maturation, so could be considered as unipotent stem cells.…”