Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML). It is unclear where in the hemopoietic hierarchy additional mutations are acquired in BP-CML, how the hemopoietic hierarchy is altered as a consequence, and the cellular identity of the resulting leukemia-propagating stem cell (LSC) populations. Here, we show that myeloid BP-CML is associated with expanded populations that have the immunophenotype of normal progenitor populations that vary between patients. Serial transplantation in immunodeficient mice demonstrated functional LSCs reside in multiple populations with the immunophenotype of normal progenitor as well as stem cells. Multicolor fluorescence in situ hybridization detected serial acquisition of cytogenetic abnormalities of chromosome 17, associated with transformation to BP-CML, that is detected with equal frequency in all functional LSC compartments. New effective myeloid BP-CML therapies will likely have to target all these LSC populations.

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

“…Apart from one report to the contrary 31 , CD34 + CD38cells are generally accepted as the principal immunophenotype in which CP-CML LSCs reside. However, LSCs in BP-CML reside in multiple immunophenotypes normally associated with less primitive hematopoietic cells 32,33 , as well as within the CD34sub-fraction 34 . In this respect, BP-CML mirrors AML, in which LSCs are also found in a variety of CD34 + and CD34immunophenotypes 23,[35][36][37] .…”

“…This is because the vast majority of CML patient samples do not engraft well in immunocompromised mice. The exception to this is in BP-CML, where the proportion of patient samples that engraft is higher than in CP-CML and often at moderate to high levels of chimerism [G] (although cohort sizes in these studies were small) 33,34,57 . For these reasons, it remains challenging to establish correlations between engraftment potential and prognosis in CP-CML or BP-CML.…”

“…and these LSCs are most similar to HSCs immunophenotypically. However, flat hierarchies also exist in both BP-CML 33 and CD34 -AML 37 , but in these situations, there are multiple seemingly independent immunophenotypes of LSCs (and in this respect these LSCs are most divergent from HSCs) that show little or no semblance of hierarchical organization. Between these two extremes lie the majority of AML cases, which display deeper, somewhat variable, hierarchies of LSCs.…”

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease

“…Despite a targeted therapeutic approach, disease persistence is driven by a small residual BCR-ABL1 positive (+) stem cell population [5][6][7][8][9]. This can lead to disease progression to the more acute form, termed blast crisis, which carries a very poor prognosis [10]. Measures to enhance the elimination of residual disease are therefore required to further improve outcomes and increase the number of patients obtaining deep molecular remission (DMR; defined as ≥4-log reduction in BCR-ABL transcript levels) who can be considered for discontinuation of TKI treatment and long-lasting treatment-free remission (TFR) [11][12][13].…”

Epigenetic Reprogramming and Emerging Epigenetic Therapies in CML

“…Research around this area is hampered due to the difficulty in isolating true BP-CML LSCs by immunophenotyping. Recent studies in patient-derived xenograft mouse models have shown that engraftable cells exist in all so-called stem and progenitor populations from BP-CML patient samples, usually a preserve of true HSCs in normal samples and CP-CML patient samples (Kinstrie et al, 2016).…”