Acute B lymphoblastic leukaemia‐propagating cells are present at high frequency in diverse lymphoblast populations

Abstract

Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-‘high-risk’ sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34high and CD34low blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

Very high frequencies of leukaemia‐initiating cells in precursor T‐acute lymphoblastic leukaemia may be obscured by cryopreservation

“…Here, cryopreservation obscured the true frequency of LSCs, which is the highest reported to date for precursor T-ALL, and among the highest cancer-initiating cell frequencies reported for any primary malignancy. Our observations for fresh cell transplants are consistent with the proposal that all blasts, or at least a very high proportion, may have leukaemia-initiating potential in some cases of human ALL (Rehe et al, 2013). Furthermore, given that the patient achieved complete morphological and molecular remission with first line chemotherapy and remains in remission 12 months from diagnosis, they also suggest, at least in this case, that existing chemotherapy regimens in ALL successfully target the great majority of cells with leukaemia-initiating potential.…”

“…In precursor B-ALL, NS xenograft-initiating cell frequencies of one in 10 5 -10 7 have been reported (Cobaleda et al, 2000), with higher frequencies observed following intrafemoral transplant into NSG mice (one in 40-10 3 ; le Viseur et al, 2008;Rehe et al, 2013) or where cells from chemorefractory patients are used (one in 10-10 2 ; Morisot et al, 2010). The cellular organization of ALL has variably been argued to be hierarchical (Cobaleda et al, 2000;Cox et al, 2007;Hong et al, 2008) or non-hierarchical (le Viseur et al, 2008Diamanti et al, 2012;Rehe et al, 2013), the latter being based on the identification of LSCs in all of the variable immunophenotypic sub-populations of the disease.…”

“…In precursor T-acute lymphoblastic leukaemia (ALL), the frequency of LSCs (defined as cells that initiate leukaemic engraftment in a xenograft recipient) is reported to range from one in 10 5 -10 7 following intravenous injection into non-obese diabetic severe combined immunodeficient (NOD/SCID; NS) mice (Cox et al, 2007;Chiu et al, 2010), or one in 10 3 -10 5 where the more immunodeficient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain is used (Armstrong et al, 2009;Chiu et al, 2010). In precursor B-ALL, NS xenograft-initiating cell frequencies of one in 10 5 -10 7 have been reported (Cobaleda et al, 2000), with higher frequencies observed following intrafemoral transplant into NSG mice (one in 40-10 3 ; le Viseur et al, 2008;Rehe et al, 2013) or where cells from chemorefractory patients are used (one in 10-10 2 ; Morisot et al, 2010). The cellular organization of ALL has variably been argued to be hierarchical (Cobaleda et al, 2000;Cox et al, 2007;Hong et al, 2008) or non-hierarchical (le Viseur et al, 2008Diamanti et al, 2012;Rehe et al, 2013), the latter being based on the identification of LSCs in all of the variable immunophenotypic sub-populations of the disease.…”

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

“…Rare self-renewing cancer stem cells give rise to more differentiated neoplastic cells with a finite life span, which account for most of the tumor mass, a concept that was also shown to be relevant in leukemic diseases, in particular AML [36]. In contrast, close to 100% of blastic B cells in human B-ALL seem to be capable of initiating the leukemia upon xenotransplantation [37,38]. The leukemia of Kit D814V transgenic mice was successfully transplanted by transfer of low numbers of cells,…”

Blinatumomab Induced Response of Multiply Refractory Multiple Myeloma in the Context of Secondary Pre-B Cell Acute Lymphoblastic Leukemia

“…The biology of Multiple Myeloma and Pre-B ALL, both B-Cell diseases, has revealed the presence of CD19 in tumor initiating cells [1,2]. Blinatumomab is a bi-specific antibody construct developed with binding domains for both CD19 and CD3 and is approved for relapsed or refractory B-cell ALL with remarkable rates of complete remission in highly refractory cases [3].…”