Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

Figures & data

Table 1 Genetic, Chromosomal, Telomere Biology and Epigenetic Modification Changes Associated with BP Transformation

	Candidates	Alterations	Features	Functions and Mechanisms
	BCR-ABL kinase domain^Citation28,Citation30^–^Citation32	Mutation	Y253F E255K	Increases carcinogenic potency, enhances autophosphorylation and tyrosine phosphorylation
			T315I	Decreases sensitivity to imatinib
	p53^Citation34,Citation36	Loss	—	Apoptosis disorder Cannot eliminate genetically defective cells
	IKZF1^Citation37	Deletion	—	Affects pre–B cell differentiation
	MYC^Citation38^–^Citation40	Upregulation	—	Mitochondrial genome instability, blocks cell growth, upregulates BCR-ABL expression, suppresses miR-150, decreases sensitivity to imatinib
Genetic Events	RUNX1^Citation44	Mutation	H78Q, D171G, R174Q, R139G, G381fster570, R174Q, V91fs-ter94	Induces BCR-ABL-expressing mice to develop mortal CML-BP-like or CML-AP-like diseases
	GATA-2^Citation46	Mutation	—	Interferes with the myelomonocytic differentiation of BCR-ABL-expressing BM hematopoietic stem/progenitor cells
	UBE2A^Citation9	Mutation	—	Abrogates myeloid cell differentiation
	PP2A^Citation51	Inactivation	—	Restoration of PP2A activity reduces the leukemic potential of BCR-ABL in vitro
	β-Catenin pathway^Citation50,Citation54	Activation	—	Enhances cell self-renewal ability Promotes DNMT1 transcription, silencing PTPRG by the hypermethylation of its promoter region
	CBL, CBLB, IDH1/2, ASXL1, TET2^Citation55	—	—	Accessory karyotypic abnormalities in advance CML
	CEBPA^Citation52,Citation53	Inactivation	—	Abrogates myeloid cell differentiation
	SOCS2, CD52	Upregulation	—	Higher frequency in the BP population
	MPO, PRAME, HLA antigens, JunB, Fos and FosB^Citation8	Downregulation	—
ACAs^Citation56,Citation58	—	Numeric Changes	+8, +21, i (17q), 3q26.2 rearrangement, +Ph, −7/7q-, +19	Higher frequency in the BP population
		Structural changes	t (1;21); t (3;21); t (7;11)	Higher frequency in the BP population; formation of the fusion protein
Telomere Biology^Citation59,Citation60,Citation62	Telomere length	Shortening	—	Higher frequency and telomere length are shorter in the BP population, accelerated telomere shortening conferring cells growth advantages
	Telomerase activity	Decreasing	—	Induces BCR-ABL-expressing cells expansion limited and stop proliferating, with morphological characteristics of apoptosis death in vitro
Epigenetic Modification^Citation63^–^Citation66	Methylated CpG	Upregulation	HIC1, MEG3 promoter, miR-147 promoter	Higher frequency in the BP population and mediates CML blast crisis transformation
		Downregulation	EPB41L3, PRDX2, PLCL1, TUSC1, BCL11B, NDRG2
	Histone modification	Increased	RBP2

Notes: This table represents the molecular mechanisms involved in CML progression.

Abbreviations: CML, chronic myeloid leukemia; AP, accelerated phase; BP blast phase; BM, bone marrow.

Figure 1 Disease progression of CML. During chronic phase, the CML stem/progenitor cells remain capable of differentiation and result in over production of mature granulocytes. In blast phase, differentiation of CML stem/progenitor has become arrested, leading to excessive accumulation of immature blasts that spill into the circulation. The biological mechanism that are responsible for CML blast transformation involves in genetic events, additional chromosomal aberrations, telomere biology and epigenetic alterations.

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