Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemi...
Blood Advances ; 2 December 2016: /DOI:doi.org/10.1182/bloodadvances.2016000810
Ross Kinstrie, Dimitris Karamitros, Nicolas Goardon, Heather Morrison, Mike Hamblin, Lisa Robinson, Richard E. Clark, Mhairi Copland and Paresh Vyas
Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating BCR-ABL 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.
Chronic phase (CP) chronic myeloid leukemia (CML), a clonal myeloproliferative disease, requires the constitutively active tyrosine kinase BCR-ABL. The majority of CP-CML patients achieve a durable complete cytogenetic response1 with tyrosine kinase inhibitors (TKIs; eg, imatinib, dasatinib, nilotinib). However, in the first few years after diagnosis, 1% to 1.5% of CP-CML patients per annum progress to a more aggressive acute leukemia, blast phase (BP)-CML. The rate of progression of CP-CML to BP-CML falls sharply when a major molecular response to TKI therapy is obtained. Less than 10% of patients present with de novo BP-CML, and two-thirds of these BP-CML patients have a myeloid immunophenotype. Response to TKIs in BP-CML is short-lived, and median survival following diagnosis of BP-CML is 6.5 to 11 months, with many patients developing additional mutations within the BCR-ABL kinase domain, leading to TKI resistance and rapid disease progression.
Recent studies of de novo acute myeloid leukemia (AML)and myelodysplastic syndrome suggest AML-initiating mutations occur in a functional stem cell compartment that could either be long-term or short-term hemopoietic stem cell (ST-HSC/multipotent progenitor [MPP]) to create pre–leukemic stem cells (pre-LSCs) that expand by clonal advantage. However, pre-LSCs still differentiate completely, or almost completely, and can be associated with normal blood counts.Additional mutations, possibly acquired in pre-LSCs or downstream pre–leukemic progenitors, are required for full transformation. In fully transformed AML, most functional leukemia-propagating stem cell (LSC) populations have global gene expression profiles and immunophenotypes most similar to normal progenitor populations (“progenitor-like”) or normal myeloid precursors, suggesting that LSCs are arrested at progenitor or precursor stages. When LSCs are arrested at progenitor-like stages, patient samples contain a mixture of expanded functional LSC populations with global RNA expression profiles most similar to lymphoid-primed multipotent progenitors (LMPP) and granulocyte-macrophage progenitors (GMP). A smaller group of patients have expanded populations that share the same immunophenotype as ST-HSC/MPP and the common myeloid progenitor (CMP). However, it is unclear if, in AML, functional LSCs exist in the ST-HSC/MPP and CMP compartments. In comparison, in CP-CML, CML propagating stem cells are contained within immunophenotypic HSC populations, and progenitors do not have extended self-renewal capacity.
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