Diverging fates of cells of origin in acute and chronic leukaemia

Abstract

The large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells – tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL-induced chronic myeloid (CML) and B-cell acute lymphoid leukaemia (B-ALL), resemble long-term haematopoietic stem cells (LT-HSCs). During disease-maintenance, CML LT-HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B-ALL LT-HSCs differentiate into CSCs that correspond to pro-B cells. This transition step requires a transient IL-7 signal and is lost in IL-7Rα-deficient cells. Thus, in BCR/ABLp185+ B-ALL and BCR/ABLp210+ CML, the final phenotype of the tumour as well as the abundance of CSCs is dictated by diverging differentiation fates of their common cells of origin.

CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

“…This procedure triggers a CMLlike disease that depends on the constant replenishment of peripheral leukemic cells by BCR-ABL p2101 LSCs. In line with published results, 37 all mice that received BCR-ABL p2101 Cdk6 1/1 BM succumbed to disease within 3 months, whereas only 1 of the 7 animals that received BCR-ABL p2101 Cdk6 2/2 cells became sick within this period ( Figure 6B). Differences were even more explicit in a second round of transplantation, which again forced the BCR-ABL For personal use only.…”

“…37 To investigate whether CDK6 regulates Egr1 in LSCs, we infected Cdk6 1/1 and Cdk6 2/2 BM cells with a retrovirus encoding BCR-ABL p210 -IRES GFP and injected them into nonirradiated NSG mice ( Figure 6A). This procedure triggers a CMLlike disease that depends on the constant replenishment of peripheral leukemic cells by BCR-ABL p2101 LSCs.…”

Modeling ETV6-JAK2-induced leukemia: insights from the zebrafish

“…Interestingly, particular breakpoints were found resulting in variant fusion proteins that were associated with different disease phenotypes. Peeters and colleagues cloned a t(9;12)(p24;p13) from a patient with early pre-B cell acute lymphoblastic leukemia (ALL) leading to a fusion of exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2, [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. In addition, they identified a t(9;15;12)(p24;q15;p13) in a patient with atypical CML in a transformation that fused exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2, 5-12).…”

“…All the mice developed an aggressive lethal mixed T-cell lympho-and myeloproliferative disease after a latency of 5-10 weeks. 8 Similarly, transgenic mice expressing the ETV6-JAK2 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) variant from an SRα promoter/enhancer element developed a fatal CD8 + T-cell acute leukemia. 11 Interestingly, breeding of the SRα-ETV6-JAK2 transgenics into a Cde-/-background with a block in T-cell development resulted in the development of B-cell lymphoma/leukemia.…”

“…CML stem cells seem to function as cancer stem cells, maintaining the disease, whereas B-ALL originating cells seem to differentiate into cancer stem cells corresponding to pro-B cells. 17 In contrast, the cellular origin of acute leukemia is less clear and seems to be primarily dependent on the type of initial driver mutation. Elegant reconstitution experiments using separately transduced flow-sorted hematopoietic stem and progenitor fractions suggested that certain oncogenes, like the MLL-AF9, MLL-ENL or the MOZ-TIF2 fusions, have leukemogenic potential in stem cells, as well as in more committed progenitors cells.…”